Buffered microencapsulated compositions and methods

ABSTRACT

A microcapsule composition comprising at least one polymer substantially disposed as a semipermeable shell around an aqueous buffered solution and at least one agent, wherein the agent permeates the shell, and wherein the composition is suitable for delivery to a mammal.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/207,545 filed Dec. 3, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/921,350 filed Mar. 14, 2018, which is acontinuation-in-part of U.S. patent application Ser. No. 15/791,554filed Oct. 24, 2017, which is a divisional of U.S. patent applicationSer. No. 13/619,128 filed Sep. 14, 2012, which is a continuation-in-partof U.S. patent application Ser. No. 12/768,696, filed Apr. 27, 2010,which claims priority of U.S. Provisional Application No. 61/172,939,filed Apr. 27, 2009, the contents of which are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

The present invention is directed to compositions, compounds and methodsfor encapsulating an aqueous buffer solution within a polymer shell toform a microcapsule, wherein the microcapsules are suitable forinclusion into a carrier for commercial products.

Microcapsules lend themselves to a diverse set of uses, and includedtherein is that certain encapsulated compounds may be suitable for oralor medicinal therapeutic use. For example, mineralized connective tissueor tissues include teeth, bone, and various connective tissues such ascollagen, cartilage, tendons, ligaments, and other dense connectivetissue and reticular fibers (that contains type III collagen) of amammal, including a human being. For purposes of definition in thisspecification, “mineralized tissue” shall mean bone and teethspecifically. Each of the terms “mineralization,” “tissuemineralization,” used interchangeably herein, means a process in whichcrystals of calcium phosphate are produced by bone-forming cells ortooth-forming cells and laid down in precise amounts within the fibrousmatrix or scaffolding of the mineralized tissue as defined hereinabove.

Calcium phosphates are a class of minerals containing, but not limitedto, calcium ions together with orthophosphates, metaphosphates, and/orpyrophosphates that may or may not contain hydrogen or hydroxide ions.

For purposes of definition in this specification, “remineralization” isthe process of restoring minerals, in the form of mineral ions, to thehydroxyapatite latticework structure of a tooth. As used herein, theterm “remineralization” includes mineralization, calcification,recalcification, and fluoridation as well as other processes by whichvarious particular ions are mineralized to the tooth. The term “teeth”or “tooth” as used herein includes the dentin, enamel, pulp, andcementum of a tooth within the oral cavity of an animal, including ahuman being.

In certain embodiments, the present invention provides methods forwhitening the surface of a tooth material by using the compositions ofthe invention. For purposes of definition in this specification, asreferred to herein, a “tooth material” refers to natural teeth,dentures, dental plates, fillings, caps, crowns, bridges, dentalimplants and the like, and any other hard surfaced dental prosthesiseither permanently or temporarily fixed to a tooth within the oralcavity of an animal, including a human being. As used herein, the terms“whitening” and “tooth whitening” used interchangeably, refer to achange in the visual appearance of a tooth as defined herein, preferablysuch that the tooth has a brighter shade or luster.

Conditions of the Bone

No currently practiced therapeutic strategy involves methods orcompositions that sufficiently stimulate or enhance the growth of newbone mass. The present invention provides compositions, products, andmethods which serve to increase bone mineralization at localized sitesor remineralization of teeth directly in the oral cavity, and thus maybe utilized in conjunction with treatments of a wide variety ofconditions where it is desired to increase bone or tissue mass as aresult of any condition which can be improved by bioavailability ofphysiological salts, particularly of calcium and phosphate.

Certain changes in bone mass occur over the life span of an individual.After about the age of 40 and continuing to the last stages of life,slow bone loss occurs in both men and women. Loss of bone mineralcontent can be caused by a variety of conditions, and may result insignificant medical problems. If the process of tissue mineralization isnot properly regulated, the result can be too little of the mineral ortoo much—either of which can compromise bone health, hardness, andstrength. A number of bone growth disorders are known which cause animbalance in the bone remodeling cycle. Chief among these are metabolicbone diseases such as osteoporosis, osteoplasia (osteomalacia), chronicrenal failure, and hyperparathyroidism, which result in abnormal orexcessive loss of bone mass known as osteopenia. Other bone diseases,such as Paget's disease, also cause excessive loss of bone mass atlocalized sites.

Osteoporosis is a structural deterioration of the skeleton caused byloss of bone mass resulting from an imbalance in bone formation, boneresorption, or both. Bone resorption is the process by which osteoclastsbreak down bone and release the minerals, resulting in a transfer ofcalcium from bone fluid to the blood. Bone resorption dominates the boneformation phase, thereby reducing the weight-bearing capacity of theaffected bone. In a healthy adult, the rate at which bone is formed andresorbed is tightly coordinated so as to maintain the renewal ofskeletal bone. However, in osteoporotic individuals, an imbalance inthese bone remodeling cycles develops which results in both loss of bonemass and in formation of microarchitectural defects in the continuity ofthe skeleton. These skeletal defects, created by perturbation in theremodeling sequence, accumulate and finally reach a point at which thestructural integrity of the skeleton is severely compromised and bonefracture is likely. Although this imbalance occurs gradually in mostindividuals as they age, it is much more severe and occurs at a rapidrate in postmenopausal women. In addition, osteoporosis also may resultfrom nutritional and endocrine imbalances, hereditary disorders, and anumber of malignant transformations.

Osteoporosis in humans is preceded by clinical osteopenia (bone mineraldensity that is greater than one standard deviation but less than 2.5standard deviations below the mean value for young adult bone), acondition found in approximately 25 million people in the United States.Another 7-8 million patients in the United States have been diagnosedwith clinical osteoporosis (defined as bone mineral content greater than2.5 standard deviations below that of mature young adult bone).Osteoporosis is one of the most expensive diseases for the health caresystem, costing billions of dollars annually in the United States. Inaddition to health care related costs, long-term residential care andlost working days add to the financial and social costs of this disease.Worldwide, approximately 75 million people are at risk for osteoporosis.

The frequency of osteoporosis in the human population increases withage, and among Caucasians is predominant in women, who compriseapproximately 80% of the osteoporosis patient pool in the United States.In addition in women, another phase of bone loss occurs possibly due topostmenopausal estrogen deficiencies. During this phase of bone loss,women can lose an additional 10% in the cortical bone and 25% from thetrabecular compartment. The increased fragility and susceptibility tofracture of skeletal bone in the aged is aggravated by the greater riskof accidental falls in this population. More than 1.5 millionosteoporosis-related bone fractures are reported in the United Stateseach year. Fractured hips, wrists, and vertebrae are among the mostcommon injuries associated with osteoporosis. Hip fractures inparticular are extremely uncomfortable and expensive for the patient,and for women correlate with high rates of mortality and morbidity.

Patients suffering from chronic renal (kidney) failure almostuniversally suffer loss of skeletal bone mass, termed renalosteodystrophy. While it is known that kidney malfunction causes acalcium and phosphate imbalance in the blood, to date replenishment ofcalcium and phosphate by dialysis does not significantly inhibitosteodystrophy in patients suffering from chronic renal failure. Inadults, osteodystrophic symptoms often are a significant cause ofmorbidity. In children, renal failure often results in a failure togrow, due to the failure to maintain and/or to increase bone mass.

Osteoplasia, also known as osteomalacia (“soft bones”), is a defect inbone mineralization (e.g., incomplete mineralization), and classicallyis related to vitamin D deficiency (1,25-dihydroxy vitamin D₃). Thedefect can cause compression fractures in bone, and a decrease in bonemass, as well as extended zones of hypertrophy and proliferativecartilage in place of bone tissue. The deficiency may result from anutritional deficiency (e.g., rickets in children), malabsorption ofvitamin D or calcium, and/or impaired metabolism of the vitamin.

Hyperparathyroidism (overproduction of the parathyroid hormone) is knownto cause malabsorption of calcium, leading to abnormal bone loss. Inchildren, hyperparathyroidism can inhibit growth, in adults the skeletonintegrity is compromised and fracture of the ribs and vertebrae arecharacteristic. The parathyroid hormone imbalance typically may resultfrom thyroid adenomas or gland hyperplasia, or may result from prolongedpharmacological use of a steroid. Secondary hyperparathyroidism also mayresult from renal osteodystrophy. In the early stages of the disease,osteoclasts are stimulated to resorb bone in response to the excesshormone present. As the disease progresses, the trabecular boneultimately is resorbed and marrow is replaced with fibrosis,macrophages, and areas of hemorrhage as a consequence of microfractures,a condition is referred to clinically as osteitis fibrosa.

Paget's disease (osteitis deformans) is a disorder currently thought tohave a viral etiology and is characterized by excessive bone resorptionat localized sites which flare and heal but which ultimately are chronicand progressive, and may lead to malignant transformation. The diseasetypically affects adults over the age of 25.

Although osteoporosis has been defined as an increase in the risk offracture due to decreased bone mass, none of the presently availabletreatments for skeletal disorders can substantially increase the bonedensity of adults. A strong perception exists among physicians thatdrugs are needed which could increase bone density in adults,particularly in the bones of the wrist, spinal column and hip that areat risk in osteopenia and osteoporosis.

Current strategies for the prevention of osteoporosis may offer somebenefit to individuals but cannot ensure resolution of the disease.These strategies include moderating physical activity, particularly inweight-bearing activities, with the onset of advanced age, includingadequate calcium in the diet, and avoiding consumption of productscontaining alcohol or tobacco. For patients presenting with clinicalosteopenia or osteoporosis, all current therapeutic drugs and strategiesare directed to reducing further loss of bone mass by inhibiting theprocess of bone absorption, a natural component of the bone remodelingprocess that occurs constitutively.

For example, estrogen is now being prescribed to retard bone loss. Thereis, however, some controversy over whether there is any long termbenefit to patients and whether there is any effect at all on patientsover 75 years old. Moreover, use of estrogen is believed to increase therisk of breast and endometrial cancer. High doses of dietary calciumwith or without vitamin D have also been suggested for postmenopausalwomen. However, ingestion of high doses of calcium can often haveunpleasant gastrointestinal side effects, and serum and urinary calciumlevels must be continuously monitored.

Other therapeutics which have been suggested include calcitonin,bisphosphonates, anabolic steroids and sodium fluoride. Suchtherapeutics however, have undesirable side effects, for example,calcitonin and steroids may cause nausea and provoke an immune reaction,bisphosphonates and sodium fluoride may inhibit repair of fractures,even though bone density increases modestly, which that may preventtheir usage.

The above disorders are examples of conditions that may lead to bonefractures, fissures or splintering of the bones in the individuals whosuffer from a given disorder. Current therapeutic methods areinsufficient to treat the disorders leaving a need for improvedtreatments of bone fractures when they occur in the individual. Thepresent invention provides improved compositions, products and methodsfor locally treating bone fractures, fissures, splintering and similarbreakages of the bone, or by strengthening decomposed bone tissue byincreasing the mechanism of mineralization of the bone. It isconceivable that the current invention also causes mineralization of thesurrounding connective tissue, such as collagen, cartilage, tendons,ligaments and other dense connective tissue and reticular fibers.

The Oral Cavity

With respect to tissue decomposition in the oral cavity, it is commonlyknown in the dental art that certain kinds of tooth decomposition anddecay that occurs over time in the mouth is initiated by acid etching ofthe tooth enamel with the source of the acid being a metaboliteresulting from bacterial and enzymatic action on food particles in theoral cavity. It is generally understood that plaque, a soft accumulationon the tooth surface consisting of an organized structure ofmicroorganisms, proteinaceous and carbohydrate substances, epithelialcells, and food debris, is a contributory factor in the development ofvarious pathological conditions of the teeth and soft tissue of the oralcavity. The saccharolytic organisms of the oral cavity which areassociated with the plaque, cause a demineralization or decalcificationof the tooth beneath the plaque matrix through metabolic activity whichresults in the accumulation and localized concentration of organicacids. The etching and demineralization of the enamel may continue untilthey cause the formation of dental caries and periodontal disease withinthe oral cavity.

Teeth are cycled through periods of mineral loss and repair also as aresult of pH fluctuations in the oral cavity. The overall loss or gainof mineral at a given tooth location determine whether the cariousprocess will regress, stabilize or advance to an irreversible state.Numerous interrelated patient factors affect the balance between theremineralization and demineralization portions of this cycle and includeoral hygiene, diet, and the quantity and quality of saliva. At the mostextreme point in this process, a restoration will be required to repairthe tooth.

Methods for the prevention and reduction of plaque and tooth decaywithin the oral cavity commonly involve the brushing of the teeth usingtoothpastes; mechanical removal of the plaque with dental floss;administration and rinsing of the oral cavity with mouthwashes,dentifrices, and antiseptics; remineralization and whitening of theteeth with fluoride agents, calcium agents and whitening agents, andvarious other applications to the oral cavity. Still missing in thefield is a delivery system for the remineralization of teeth that wouldaddress the challenges of demineralization facing the teeth continuallyin the oral cavity.

A tooth that has reached an advanced stage of decay often requiresinstallation of a dental restoration within the mouth. Half of alldental restorations fail within 10 years, and replacing them consumes60% of the average dentist's practice time. Current dental materials arechallenged by the harsh mechanical and chemical environment of the oralcavity with secondary decay being the major cause of failure.Development of stronger and longer-lasting biocompatible dentalrestorations by engineering novel dental materials or new resin systems,enhancing existing materials, and incorporating bioactive agents inmaterials to combat microbial destruction and to sustain the harshmechanical and chemical environment of the oral cavity continues to bedesired.

Despite numerous preventive oral health strategies, dental cariesremains a significant oral health problem. More than 50% of childrenaged 6-8 will have dental caries and over 80% of adolescents over age 17will have experienced the disease. Caries is also seen in adults both asa primary disease and as recurrent disease in already treated teeth.Advances in diagnosis and treatment have led to noninvasiveremineralizing techniques to treat caries. However mechanical removal ofdiseased hard tissue and restoration and replacement of enamel anddentin is still the most widely employed clinical strategy for treatingprimary caries, restoring function to the tooth and also blockingfurther decay. In addition, nearly 50% of newly placed restorations arereplacement of failed restorations. Clearly, restorative materials are akey component of treating this widespread disease.

The selection of a restorative material has significantly changed inrecent years. While dental amalgam is still considered a cost effectivematerial, there is a growing demand for tooth colored alternatives thatwill provide the same clinical longevity that is enjoyed by dentalamalgam. The use of composite resins has grown significantlyinternationally as a material of choice for replacing amalgam as arestorative material for posterior restorations. This demand ispartially consumer driven by preference for esthetic materials and theconcerns regarding the mercury content of amalgam. It is also driven bydentists recognizing the promise of resin-based bonded materials inpreserving and even supporting tooth structure. Numerous studies havesuggested that bonding the restoration to the remaining tooth structuredecreases fracture of multisurface permanent molar preparations.Unfortunately, posterior teeth restored with direct resin restorativematerials have a higher incidence of secondary caries. This has led toshorter clinical service and narrower clinical indications for compositeresin materials compared to amalgam.

The most frequently cited reason for restoration replacement isrecurrent decay around or adjacent to an existing restoration. It islikely that fracture at the margin due to polymerization shrinkage canlead to a clinical environment at the interface between a restorationand the tooth that collects dental plaque and thus promotes decay.Therefore, developing dental materials with anticaries capability is avery high priority for extending the longevity of restorations.

Tooth Remineralization

Although natural remineralization is always taking place in the oralcavity, the level of activity varies according to conditions in themouth as discussed. Incorporation of fluoride during theremineralization process has been a keystone for caries prevention. Theeffectiveness of fluoride release from various delivery platforms,including certain dental restorative materials has been widelydemonstrated. It is commonly accepted that caries prevention fromfluoride is derived from its incorporation as fluorapatite or fluorideenriched hydroxyapatite in the tooth mineral thereby decreasing thesolubility of tooth enamel. More recently, anticaries activity has beendemonstrated using the strategy of increasing solution calcium andphosphate concentrations to levels that exceed the ambient concentrationin oral fluids. In order for fluoride to be effective at remineralizingpreviously demineralized enamel, a sufficient amount of calcium andphosphate ions must be available. For every two (2) fluoride ions, ten(10) calcium ions and six (6) phosphate ions are required to form a cellof fluorapatite (Ca₁₀(PO₄)₆F₂). Thus the limiting factor for net enamelremineralization is the availability of calcium and fluoride in saliva.

The low solubility of calcium phosphates has limited their use inclinical delivery platforms, especially when in the presence of fluorideions. These insoluble phosphates can only produce available ions fordiffusion into the enamel in an acidic environment. They do noteffectively localize to the tooth surface and are difficult to apply inclinically usable forms. Because of their intrinsic solubility, solublecalcium and phosphate ions can only be used at very low concentrations.Thus they do not produce concentration gradients that drive diffusioninto the subsurface enamel of the tooth. The solubility challenge isexacerbated by the even lower solubility of calcium fluoride phosphates.

Several commercially available approaches exist using calcium andphosphate preparations that have been commercialized into various dentaldelivery models. These have been reportedly compounded to overcome thelimited bioavailability of calcium and phosphate ions for theremineralization process. The first technology uses caseinphosphopeptide (CCP) stabilized with amorphous calcium phosphate (ACP)(RECALDENT® CCP-ACP of Cadbury Enterprises Pte. Ltd.). It ishypothesized that the casein phosphopeptide can facilitate thestabilization of high concentrations of ionically available calcium andphosphate even in the presence of fluoride. This formulation binds topellicle and plaque and while the casein phosphopeptide prevents theformation of dental calculus, the ions are available to diffuse down theconcentration gradient to subsurface enamel lesions facilitatingremineralization. As compared to the CCP-ACP, in the composition of theinvention, biologically available ions are available due to the factthat the salts are already solvated in the microcapsule of theinvention. Amorphous calcium phosphate is not soluble in water orsaliva. Although the manufacturer claims release of bioavailable ionsfrom amorphous calcium phosphate, it is not as a result of thedissolution of the complex. A second technology (ENAMELON®) usesunstabilized amorphous calcium phosphate. Calcium ions and phosphateions are introduced as a dentifrice separately in a dual chamber deviceforming amorphous calcium phosphate in-situ. It is proposed thatformation of the amorphous complex promotes remineralization. A thirdapproach uses a so-called bioactive glass (NOVAMIN® of NovaMinTechnology Inc.) containing calcium sodium phosphosilicate. It isproposed that the glass releases calcium and phosphate ions that areavailable to promote remineralization. More recently dental compositeformulations have been compounded using zirconia-hybridized ACP that mayhave the potential for facilitating clinical remineralization.

While the Recaldent® and Enamelon® preparations have both in-situ andin-vivo evidence suggesting enhanced remineralization, these aretopically applied and do not specifically target the most at risklocation for recurrent caries at the tooth restoration interface. Whilethe bioactive glass and the zirconia-hybridized-ACP filler technologieshave potential, they are relatively inflexible in terms of the range offormulations in which they might be used due to the challenges ofdealing with brittle fillers and some of the limitations on controllingfiller particle size.

Another approach taken to decrease caries in the oral cavity is thelimiting of demineralization of enamel and bone by drinking waterfluoridation. It has been shown that the fluoride contained in drinkingwater incorporates to some extent into hydroxyapatite, the majorinorganic component of enamel and bone. Fluoridated hydroxyapatite isless susceptible to demineralization by acids and is thus seen to resistthe degradation forces of acidic plaque and pocket metabolites. Inaddition, fluoride ion concentration in saliva is increased throughconsumption of fluoridated drinking water. Saliva thus serves as anadditional fluoride ion reservoir and in combination with bufferingsalts naturally found in salivary fluid, fluoride ions are activelyexchanged on the enamel surface, further offsetting the effects ofdemineralizing acid metabolites.

Notwithstanding the established benefits of fluoride treatment of teeth,fluoride ion treatment can result in irregular spotting or blotching ofthe teeth depending on the individual, whether administered throughdrinking water or by topically applied fluoride treatment. This effectis known to be both concentration related and patient specific. Inaddition, the toxicology of fluoride is being studied as to its longterm effect on human health. Desired is a targeted approach offluoridation in the oral cavity.

Another approach to limiting the proliferation of microflora in the oralenvironment is through topical or systematic application ofbroad-spectrum antibacterial compounds. Reducing the number of oralmicroflora in the mouth results in a direct reduction or elimination ofplaque and pocket accumulation together with their damaging acidicmetabolite production. The major drawback to this particular approach isthat a wide variety of benign or beneficial strains of bacteria arefound in the oral environment which may be killed by the sameantibacterial compounds in the same manner as the harmful strains. Inaddition, treatment with antibacterial compounds may select for certainbacterial and fungi, which may then become resistant to theantibacterial compound administered and thus proliferate, unrestrainedby the symbiotic forces of a properly balanced microflora population.Thus the application or administration of broad-spectrum antibioticsalone is ill-advised for the treatment of caries and a more specific,targeted approach is desired.

Tooth Whitening

Cosmetic dental whitening or bleaching has become extremely desirable tothe general public. Many individuals desire a “bright” smile and whiteteeth, and consider dull and stained teeth cosmetically unattractive.Unfortunately, without preventive or remedial measures, stained teethare almost inevitable due to the absorbent nature of dental material.Everyday activities such as eating, chewing, or drinking certain foodsand beverages (in particular coffee, tea, and red wine) and smoking orother oral use of tobacco products cause undesirable staining ofsurfaces of teeth. Extrinsic staining of the acquired pellicle arises asa result of compounds such as tannins and polyphenolic compounds whichbecome trapped in and tightly bound to the proteinaceous layer on thesurfaces of teeth. This type of staining can usually be removed bymechanical methods of tooth cleaning. In contrast, intrinsic stainingoccurs when staining compounds penetrate the enamel and even the dentinor arise from sources within the tooth. The chromogens or color causingsubstances in these materials become part of the pellicle layer and canpermeate the enamel layer. Even with regular brushing and flossing,years of chromogen accumulation can impart noticeable toothdiscoloration. Intrinsic staining can also result from microbialactivity, including that associated with dental plaque. This type ofstaining is not amenable to mechanical methods of tooth cleaning andchemical methods are required.

Without specifically defining the mechanism of action of the presentinvention, the compositions, products and methods of the presentinvention enable the precipitation of salts onto the surfaces of theteeth in the oral cavity and make the salts available for adherence tothe tooth surface and remineralization of the teeth. The mineralizingsalts are deposited in the interstitial spaces of the teeth, making theteeth smoother, increasing the reflection of light from the surface ofthe teeth and thereby giving the teeth a brighter, more lustrousappearance and whiter visual effect.

Tooth whitening compositions generally fall into two categories: (1)gels, pastes, varnishes or liquids, including toothpastes that aremechanically agitated at the stained tooth surface in order to affecttooth stain removal through abrasive erosion of stained acquiredpellicle; and (2) gels, pastes, varnishes or liquids that accomplish thetooth whitening effect by a chemical process while in contact with thestained tooth surface for a specified period, after which theformulation is removed. In some cases, the mechanical process issupplemented by an auxiliary chemical process which may be oxidative orenzymatic. Initially, tooth whitening had been performed at thedentist's office. Less expensive at-home dental whitening kits havebecome available, such as whitening strips and whitening trays that comein either single compartment or dual compartment systems.

Both in-office and at-home tooth whitening typically involves theapplication of a peroxide containing composition to the surface of thetooth to achieve the desired whitening effect. The majority of mostin-office and at-home tooth whitening compositions act by oxidation.These compositions are applied directly by a patient in a toothbleaching tray, held in place in the mouth for contact times, sometimesfor periods of half an hour several times per day; or of greater than 60minutes per day, and sometimes as long as 8 to 12 hours. The slow rateof bleaching is, in large part, the consequence of formulations that aredeveloped to maintain stability of the oxidizing composition. Aqueoustooth whitening gels have proven desirable due to the hydrating effectson the structure of the tooth, reducing the likelihood of toothsensitivity.

The most commonly used oxidative compositions contain the hydrogenperoxide precursor carbamide peroxide which is mixed with an anhydrousor low water content, hygroscopic viscous carrier containing glycerineand/or propylene glycol and/or polyethylene glycol. When contacted bywater, carbamide peroxide dissociates into urea and hydrogen peroxide.The latter has become the tooth bleaching material of choice due to itsability to whiten teeth faster than higher concentrations of carbamideperoxide.

An alternative source of hydrogen peroxide is sodium percarbonate andthis has been used in a silicone polymer product that is painted ontothe teeth forming a durable film for overnight bleaching procedures. Theperoxide is slowly released for up to 4 hours.

Associated with the slow rate of bleaching in the hygroscopic carrier,the currently available tooth bleaching compositions cause toothsensitization in over 50% of patients. Tooth sensitivity is believed toresult from the movement of fluid through the dentinal tubes towardnerve endings in the tooth. This movement is enhanced by the carriersfor the carbamide peroxide. It has been determined that glycerine,propylene glycol and polyethylene glycol can each give rise to varyingamounts of tooth sensitivity following exposure of the teeth to heat,cold, overly sweet substances, and other causative agents.

Hydrogen peroxide tooth bleaching formulations have limitations inaddition to tooth sensitivity. Until recent years, stable aqueoushydrogen peroxide tooth bleaching gels have been virtually nonexistent.Hydrogen peroxide is a powerful oxidizing agent and an unstable compoundthat decomposes readily over time into water and oxygen. Certainchemical and physical influences in the oral cavity can accelerate therate of decomposition and need to be controlled for a stable toothwhitening gel to exist. Temperature, pH and errant metal ions all have aprofound effect on the decomposition of hydrogen peroxide, particularlyin an aqueous formula.

One advantage of the compositions of the invention is the decrease orelimination of tooth sensitivity of the patient. When used inconjunction with current tooth bleaching products, the microcapsules ofthe invention release salt ions that precipitate as salts in the oralcavity and mineralize the open dentin tubules of the teeth therebydecreasing tooth sensitivity to the oxidative tooth bleaching product.

Whitening systems on the market include two-part systems that requiremixing of the components upon administration and single partcompositions that are faster and easier to administer and generallypreferred for in-office bleaching by dentists. Two-part systems includeproducts such as dual barrel syringes, liquid hydrogen peroxide/powdersystems and whitening strips. Single component tooth bleachingcompositions prefer room temperature storage conditions in order toeliminate costly and inconvenient storage problems. The pH of an aqueoushydrogen peroxide tooth whitening composition also has great bearing onthe stability of the formulation. The two-part systems demonstratesuperior shelf life stability. Formulations that contain hydrogenperoxide solutions are strongly acidic and maintain their stability inacidic pH formulas. Stable aqueous hydrogen peroxide tooth whiteninggels can be formulated in the acid pH range. However, bleachingcompositions in the acidic pH range (pH 2.0-5.5) are prone to thedemineralization of dental enamel by the solubilizing of calcium ionsfrom the tooth surface. This reduction in surface enamel leads to toothsensitivity and discomfort for the patient. By incorporating thecompositions of the invention into tooth bleaching products or utilizingthem in conjunction with tooth bleaching products, the microcapsules ofthe invention can modify the pH level in the oral cavity to causeacceleration of the bleaching process.

Many of the available products are time-consuming and limited in theireffectiveness and subject the user to various physical discomforts. Moreimportantly, it has been shown that prolonged exposure of teeth towhitening compositions, as practiced at present, has a number of adverseeffects in addition to that of tooth sensitivity. Over time, any of theperoxides known in the art to achieve a desired tooth bleaching effectwill function as calcium chelating agents. Other examples of chelationagents often found in tooth whitening products include EDTA and itssalts, citric acid and its salts, gluconic acid and its salts, alkalimetal pyrophosphates and alkali metal polyphosphates. Solubilization ofcalcium from the enamel layer can occur at a pH less than 5.5 withassociated demineralization. The chelating agents will penetrate theintact enamel and dentin so as to reach the pulp chamber of a vitaltooth thereby risking damage to pulpal tissue. Other adverse effectsinclude dilution of the bleaching compositions with saliva in the oralcavity with resulting leaching from the dental tray and subsequentdigestion by the user.

It has been shown that the rate of whitening can be increased byincreasing the temperature of the hydrogen peroxide system, whereincrease of 10° C. can double the rate of reaction. Consequently, thereexist a number of procedures that utilize high intensity light to raisethe temperature of the hydrogen peroxide to accelerate the rate ofbleaching of the teeth. Other approaches to heating the hydrogenperoxide have been described such as the heating of dental instruments.Contemporary approaches and literature have focused on acceleratingperoxide bleaching with simultaneous illumination of the anterior teethwith various sources having a range of wavelengths and spectral power,for example, halogen curing lights, plasma arc lamps, lasers andlight-emitting diodes. Some products that are used in light activatedwhitening procedures contain ingredients that serve as photosensitizersthat claim to aid the energy transfer from the light to the peroxide geland are often colored materials, for example carotene and manganesesulfate. However, excessive heating can cause irreversible damage to thedental pulp. In addition, the literature for in vitro and clinicalstudies and actual results demonstrate that the actual effect of lighton tooth whitening is limited, conflicting and controversial.

There is thus a need for improved compositions, methods and productsthat overcome the limitations of the prior art. The challenge remains tocreate a tooth whitening and remineralization technology platform forincorporating stable and effective tissue remineralization ions that canbe incorporated into a myriad of dental materials and variety ofproducts. Such a delivery platform would facilitate the formulation ofdental products capable of remineralization of the teeth. Thecompositions, products and methods of the current inventions asdescribed herein satisfy these and other needs. The ultimate impact is areduction in recurrent caries, the most prevalent reason for restorationreplacement; whitening of the teeth; and resulting improvement inoverall strength and health of the teeth in the oral cavity.

Consumer products using therapeutic and nontherapeutic materials. Thereare also broad classes of cleaning products, solvents, detergents,dishwashing liquids, personal care products, fabric care products, odorrelated materials, creams, gels, and foams for personal care or homecare, hair care products, cosmetics, nutritional supplements,deodorants, skin care products, cosmetic products, insect controlmaterials, industrial materials, and absorptive materials includingdiapers, absorbent paper, animal waste absorbents, and other materialsin common usage. Many of these products could benefit from the additionof additives or therapeutics. However, adding such components to thesematerials, to date, is difficult or problematic for stability reasons orfor degradation of the additive or of the product themselves.

There exists a broad need for improved compositions and methods usefulfor therapeutic and nontherapeutic agent delivery. In particular, thereis a need for an improved microcapsules, encapsulating an aqueous buffersolution, for delivering agents within carrier.

SUMMARY OF THE INVENTION

In accordance with the description herein and desire to provide improvedtherapeutic products, the present invention provides compositions andmethods that deliver a buffered therapeutic agent in a controlledfashion. Also presented are methods for using such compositions in thetreatment and prevention of a wide variety of conditions resulting frommicroorganisms. The invention also provides compositions and productsfor antimicrobial coatings. More particularly, the present inventionprovides a composition comprising aqueous buffered solutions ofadditives or therapeutic agents encapsulated in a semipermeable polymershell that allows the release of additive or agents to be delivered. Themicrocapsules can be incorporated into a variety of products asdiscussed herein, and can be prepared by any generally knownmicroencapsulation method, but preferably by surfactant-free inverseemulsion.

More particularly, the invention includes a composition containingpolymer microencapsulated solutions of aqueous buffered additivesprovided within a carrier. Further, the rate of release of thetherapeutic agent from the microcapsules can be designed in a singletype of microcapsule and in a product containing a number of differenttypes of microcapsules. This results in controlled time release of theadditive, thereby allowing release of the additive over a prolongedperiod of time.

In a preferred embodiment, a microcapsule formulation comprising aplurality of microcapsules and a carrier, each of said microcapsuleshaving a semipermeable shell and encapsulating therein a bufferedsolution and an additive, wherein said buffered solution is in contactwith the semipermeable shell, and a carrier, wherein the microcapsulesare substantially disposed within the carrier.

In a preferred embodiment, the additive is a solute within the bufferedsolution. In certain embodiments, the buffered solution is an aqueoussolution.

In a preferred embodiment, the microcapsule formulation, wherein saidadditive is selected from the group consisting of: an antimicrobialagent, antifungal agent, antibacterial agent, antiviral agent,antiparasitic agent, pesticide, anticoagulant, antithrombotic,anticancer agent, anti-inflammatory, antiplaque, desensitizing agent, adye, a colorant, a deodorant, a flavorant, a fabric softener, adetergent, a soap, a drying agent, a wetting agent, and a perfume orscented agent.

In a preferred embodiment, the microcapsule formulation according to theembodiment above, wherein the anitimicrobial agents are selected fromthe group consisting of: natural antimicrobial agents, beta lactamantibiotics such as penicillins or cephalosporins, protein synthesisinhibitors, aminoglycosides, macrolides, ketolides, tetracyclines,chloramphenicol, and polypeptides; penicillins include: penicillin G,procaine penicillin, benzathine penicillin, and penicillin V;cephalosporins include: cefacetrile, cefadroxil, cephalexin,cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin,cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine,ceftezole, cefaclor, cefonicid, cefprozil, cefuroxime, cefuzonam,cefmetazole, cefotetan and cefoxitin; aminoglycosides include, but arenot limited to, amikacin, arbekacin, gentamicin, kanamycin, neomycin,netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin,and apramycin; macrolides include: azithromycin, clarithromycin,dirithromycin, erythromycin, roxithromycin, and telithromycin; ketolidesinclude, but are not limited to, telithromycin, cethromycin,solithromycin, spiramycin, ansamycin, oleandomycin, carbomycin andtylosin; naturally occurring tetracyclines include: tetracycline,chlortetracycline, oxytetracycline, and demeclocycline; semisynthetictetracyclines include, but are not limited to, doxycycline, lymecycline,meclocycline, methacycline, minocycline and rolitetracycline;polypeptides include, but are not limited to, actinomycin, bacitracin,colistin, and polymyxin B; synthetic antimicrobial agents include:sulphonamides, cotrimoxazole, quinolones, antivirals, antifungals,anticancer drugs, antimalarials, antituberculosis drugs, antileproticsand antiprotozoals; sulphonamide antibacterials may include:sulfamethoxazole, sulfisomidine, sulfacetamide, sulfadoxine,dichlorphenamide, and dorzolamide; sulphonamide diuretics include:bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide,indapamide, mefruside, metolazone, and xipamide; sulphonamideanticonvulsants include, but are not limited to, acetazolamide,ethoxzolamide, sultiame and zonisamide; sulfonamide therapeutic agentsinclude: celecoxib, darunavir, probenecid, sulfasalazine, sumatriptan,and combinations thereof.

In a preferred embodiment, the microcapsule formulation according to theabove embodiment, wherein the antifungal agent is selected from thegroup consisting of: polyene type, amphotericin B, candicidin, filipin,hamycin, natamycin, nystatin and rimocidin; imidazole, triazole, andthiazole types which include: bifonazole, butoconazole, clotrimazole,econazole, fenticonazole, isoconazole, ketoconazole, miconazole,omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole,albaconazole, fluconazole, isavuconazole, itraconazole, posaconazole,ravuconazole, terconazole, voriconazole and abafungin; echinocandinsincluding: anidulafungin, caspofungin, micafungin, and combinationsthereof.

In a preferred embodiment, the microcapsule formulation according to theabove embodiments, wherein the antibacterial additive is selected fromthe group consisting of: copper (II) compounds including: copper (II)chloride, fluoride, sulfate and hydroxide, zinc ion sources including:zinc acetate, zinc citrate, zinc gluconate, zinc glycinate, zinc oxide,zinc sulfate and sodium zinc citrate, phthalic acid and salts thereofincluding: magnesium monopotassium phthalate, hexetidine, octenidine,sanguinarine, benzalkonium chloride, domiphen bromide, alkylpyridiniumchlorides including: cetylpyridinium chloride (CPC) (includingcombinations of CPC with zinc and/or enzymes), tetradecylpyridiniumchloride and N-tetradecyl-4-ethylpyridinium chloride, iodine,halogenated carbanilides, halogenated salicylanilides, benzoic esters,halogenated diphenyl ethers, and mixtures thereof diphenyl etherinscluding: 2,4,4′-trichloro-2′-hydroxydiphenyl ether (Triclosan) and2,2′-dihydroxy-5,5′-dibromodiphenyl ether; allylamines agents including:butenafine, naftifine, terbinafine, and combinations thereof.

In a preferred embodiment, the microcapsule formulation of the aboveembodiments, wherein the antiparasitic agent is selected from the groupconsisting of: Broad-spectrum, Nitazoxanide, Antiprotozoals Melarsoprol,Eflornithine, Metronidazole, Tinidazole, Miltefosine, Antihelminthic,Antinematodes, Mebendazole, Pyrantel pamoate, Thiabendazole,Diethylcarbamazine, Ivermectin, Anticestodes, Niclosamide, Praziquantel,Albendazole, Antitrematodes, Antiamoebics, Rifampin and Amphotericin B;Fumagillin, alinia, benznidazole, daraprim, humatin, iodoquinol,nitazoxanide, paromomycin, pyrimethamine, tindamex, tinidazole, yodoxin,and combinations thereof.

In a preferred embodiment, the microcapsule formulation wherein thecarrier is a soap, a laundry detergent, an antibacterial cleaningproduct, an antifungal cleaning product, a skincare product, a shampoo,a conditioner, a hair gel, or a hair dye.

In a preferred embodiment, the microcapsule formulation wherein saidplurality of microcapsules comprises a first microcapsule and a secondmicrocapsule, said first microcapsule having a different property thansaid second microcapsule. In a preferred embodiment, the microcapsuleformulation wherein the first microcapsule is formed from a differentpolymer than the second microcapsule. In a further preferred embodiment,the microcapsule formulation wherein the first microcapsule has adifferent release profile than the second microcapsule. In a preferredembodiment, the microcapsule formulation wherein the first microcapsuleencapsulates a first additive and the second microcapsule encapsulates adifferent second additive. In a preferred embodiment, the microcapsuleformulation wherein the first and second microcapsules encapsulate thesame additive.

A preferred embodiment is directed towards a method of manufacturing amicrocapsule comprising: contacting an aqueous buffered solutioncomprising an additive to an oil phase, a polymer, and an emulsifyingagent, forming microcapsules through a surfactant-free inverse emulsionof water in oil, wherein the polymer substantially forms a semipermeableshell around the aqueous buffered solution.

In a preferred embodiment, the method of manufacture of a microcapsule,wherein the oil phase is a hydrophobic oil; and wherein the emulsifyingagent that serves to sterically stabilize the dispersed phase. In apreferred embodiment, the method wherein the oil phase is methylbenzoate.

In a preferred embodiment, methods of manufacturing the microcapsule,wherein the polymer is selected from the group consisting of: acrylicpolymers, alkyl resins, aminoplasts, coumarone-indene resins, epoxyresins, fluoropolymers, phenolic resins, polyacetals, polyacetylenes,polyacrylics, polyalkylenes, polyalkenylenes, polyalkynylenes, polyamicacids, polyamides, polyamines, polyanhydrides, polyarylenealkenylenes,polyarylenealkylenes, polyarylenes, polyazomethines, polybenzimidazoles,polybenzothiazoles, polybenzoxazinones, polybenzoxazoles, polybenzyls,polycarbodiimides, polycarbonates, polycarboranes, polycarbosilanes,polycyanurates, polydienes, polyester-polyurethanes, polyesters,polyetheretherketones, polyether-polyurethanes, polyethers,polyhydrazides, polyimidazoles, polyimides, polyimines,polyisocyanurates, polyketones, polyolefins, polyoxadiazoles,polyoxides, polyoxyalkylenes, polyoxyarylenes, polyoxymethylenes,polyoxyphenylenes, polyphenyls, polyphosphazenes, polypyrroles,polypyrrones, polyquinolines, polyquinoxalines, plysilanes,polysilazanes, polysiloxanes, polysilsesquioxanes, polysulfides,polysulfonamides, polysulfones, polythiazoles, polythioalkylenes,polythioarylenes, polythioethers, polythiomethylenes,polythiophenylenes, polyureas, polyurethanes, polyvinyl acetals,polyvinyl butyrals, polyvinyl formals, and combinations thereof. Inpreferred embodiments, the polymer is an amphiphilic polyurethanepolymer having a molecular weight between 1,000 g/mol to 20,000 g/mol.

In a preferred embodiment, a method of manufacture of a microcapsule asprovided herein, wherein the buffer solution comprises: phosphatebuffered saline which is a solution containing sodium chloride, sodiumphosphate, or potassium chloride, or potassium phosphate;3-([tris(hydroxymethyl)methyl]amino) propane-sulfonic acid (TAPS);N,N-bis(2-hydroxyethyl)glycine (Bicine);tris(hydroxyl-methyl)methylamine (Tris);N-tris(hydroxymethyl)methylglycine (Tricine);3-[N-Tris-(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid(TAPSO); 4-2-hydroxy-ethyl-1-piperazineethanesulfonic acid (HEPES);2-([tris(hydroxymethyl)methyl]amino) ethanesulfonic acid (TES);3-(N-morpholino)propanesulfonic acid (MOPS);piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES); dimethylarsinic acid(Cacodylate); saline sodium citrate (SSC);2-(N-morpholino)ethanesulfonic acid (MES); Phosphoric acid; citric acid;piperazine-N,N′-bis(3-propanesulfonic acid (PIPPS);piperazine-N,N′-bis(3-butanesulfonic acid) (PIPBS);N,N′-Diethylethylenediamine-N,N′-bis(3-propanesulfonic acid) (DESPEN);N,N′-di ethyl piperazine dihydrochloride (DEPP.2HC1);N,N,N′,N′-tetraethyl-ethylenediamine dihydrochloride (TEEN.2HC1);N-2-Acetamidoiminodiacetic acid (ADA);1,3-Bis[tris(hydroxymethyl)methylamino]propane hydrochloride (BIS-TRISpropane.HCl); N-2-acetamido-2-aminoethanesulfonic acid (ACES);3-(N-Morpholino)-2-hydroxypropanesulfonic acid (MOPSO); imidazolehydrochloride; 3-(N-morpholino)butanesulfonic acid (MOBS);4-2-hydroxyethyl-1-piperazinepropane-sulfonic acid (HEPPS);N-tris(hydroxymethyl)methylglycine (TRICINE); glycine amidehydrochloride; Tris(hydroxymethyl)aminomethane hydrochloride (TRIShydrochloride); glycylglycine; Boric acid; cyclohexylaminoethanesulfonicacid (CHES); 3-(Cyclohexylamino)propane sulfonic acid (CAPS);N,N,N′,N′-tetraethylmethylene-diamine dihydrochloride (TEMN.2HC1); HCland sodium citrate; citric acid and sodium citrate; acetic acid andsodium acetate; K₂HPO₄ and KH₂PO₄; Na₂HPO₄ and NaH₂PO₄;N-cyclohexyl-2-aminoethanesulfonic acid; sodium borate; and sodiumhydroxide.

In a preferred embodiment, an aqueous buffer solution is at a pH ofbetween 3 and 12.

In a preferred embodiment, a method of forming the microcapsules furthercomprising a diol added to the system to increase the molecular weightof an isocyanate functionalized polyurethane shell.

In certain preferred embodiments, the microcapsules are biodegradable.

In certain preferred embodiments, the microcapsule is nonbiodegradable.

In certain methods, the emulsifying agent is in a continuous oil phase,said emulsifying agent sufficient to sterically stabilize the dispersedwater droplets to allow the formation of interfacial polymerization toform the microcapsules.

In a preferred embodiment of a microcapsule formulation, wherein themicrocapsule formulation is formulated into a shampoo, a conditioner, ahair gel, a hair foam, a shaving creme, a hair dye, a cleanser, a soap,a moisturizer, a paint, a lacquer, a nail polish, a detergent, aninsecticide, an antiparasitic, an antifungal, an antibacterial, adeodorant, and a pesticide.

In a preferred embodiment of a microcapsule formulation, an additive toa microcapsule is selected from the group consisting of a sweetenerselected from: natural or artificial, nutritive or nonnutritivesweeteners, dextrose, polydextrose, sucrose, maltose, dextrin, driedinvert sugar, mannose, xylose, ribose, fructose, levulose, galactose,corn syrup (including high fructose corn syrup and corn syrup solids),partially hydrolyzed starch, hydrogenated starch hydrolysate, sorbitol,mannitol, xylitol, maltitol, isomalt, aspartame, neotame, saccharin andsalts thereof, sucralose, dipeptidebased intense sweeteners, cyclamates,dihydrochalcones, and mixtures thereof. In a preferred embodiment, theadditive is a biologically active additive. In a preferred embodiment,the additive is a peptide-based or peptide analog-based antimicrobialagent, which is embedded in a surface coating.

In a preferred embodiment of a microcapsule formulation, the additive ina microcapsule is a natural or synthetic flavorant selected from:flavoring oils, flavoring aldehydes, esters, alcohols, similarmaterials, and combinations thereof, vanillin, sage, marjoram, parsleyoil, spearmint oil, cinnamon oil, oil of wintergreen (methylsalicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptusoil, citrus oils, fruit oils and essences including those derived fromlemon, orange, lime, grapefruit, apricot, banana, grape, apple,strawberry, cherry, pineapple, bean- and nut-derived flavors such ascoffee, cocoa, cola, peanut, and almond.

In a preferred embodiment of a microcapsule formulation, the additive isselected from the group consist of: menthol, menthyl acetate, menthyllactate, camphor, eucalyptus oil, eucalyptol, anethole, eugenol, cassia,oxanone, a-irisone, propenyl guaiethol, thymol, linalool, benzaldehyde,cinnamaldehyde, N-ethyl-p-menthan-3-carboxamine,N,2,3trimethyl-2-isopropylbutanamide, 3-1-menthoxypropane-1, 2-diol,cinnamaldehyde glycerol acetal (CGA), methone glycerol acetal (MGA), andmixtures thereof.

In a preferred embodiment of a microcapsule formulation, an additive isselected from the group consist of: butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), vitamin A, carotenoids, vitamin E,flavonoids, polyphenols, ascorbic acid, herbal antioxidants,chlorophyll, melatonin, and mixtures thereof.

In a preferred embodiment of a microcapsule formulation the additive isselected from the group consist of: Halogenated hydrocarbons selectedfrom: salicylanilides, carbanilides, bisphenols, diphenyl ethers,anilides of thiophene carboxylic acids and chlorhexidines; Quaternaryammonium compounds selected from: alkyl ammonium, pyridinum, andisoquinolinium salts, and Sulfur active compounds selected from: thiuramsulfides and dithiocarbamates, and combinations thereof.

A preferred embodiment is directed towards a formulation comprising acarrier and a microcapsule, said microcapsule comprising at least onepolymer substantially disposed as a shell around an aqueous bufferedsolution of at least one additive; wherein the microcapsule is disposedof within said carrier and remains inactive within said carrier. In apreferred embodiment, the formulation wherein the microcapsule is formedby a surfactant-free inverse emulsion interfacial polymerization bycontacting the aqueous buffered solution with an oil phase, the at leastone polymer, and an emulsifying agent. In a preferred embodiment, theformulation wherein the polymer is an amphiphilic polymer having amolecular weight of between 1,000 g/mol and 20,000 g/mol. In a preferredembodiment, the formulation further comprising a diol, an isocyanate, orboth. In a further embodiment, the formulation wherein the oil phase ismethyl benzoate and wherein the emulsifying agent ispolyglyceryl-3-polyricinoleate.

A preferred embodiment is directed towards microcapsules, encapsulatingbuffered solution with self-replicating peptides; providing an enhancedstability for the peptide in the formulation.

In a preferred embodiment, a microcapsule formulation is generatedcomprising a consumer care product, and a microcapsule providing for adelayed release of an active agent suitable for addressing the consumercare issue.

In a preferred embodiment, a microcapsule formulation is provided in acarrier that is a cosmetology product, including makeups, foundations,liners, lipsticks, blush, concealers, and perfumes.

In a preferred embodiment, microcapsules are formulated into personalcare products, including moist tissues, hygiene products, deodorants,and antiperspirants.

In a preferred embodiment, microcapsules are formulated into a soap orcleaning product. Wherein the microcapsule may include a furthercleaning agent, allowing for extended release of cleaning agents to asurface. In further embodiments, the microcapsule comprises a scentedcomposition, a drying agent, an antibacterial, an antimicrobial, or anantifungal composition, or a combination thereof.

In a preferred embodiment, a microcapsule formulation in a skincareproduct such as a moisturizer, skin protectant, antibiotic agent, ortopical wound dressing.

A preferred embodiment is directed towards a home care product fortreating parasites or insects.

In a preferred embodiment a laundry detergent, providing a microcapsulehaving a fabric softener, a scented material, an antifungal, orcombinations thereof.

A method of forming a hair care product comprising a microcapsulecomprising: forming a plurality of semipermeable microcapsules bysurfactant-free inverse emulsion interfacial polymerization, wherein themicrocapsules by contacting (a) water, (b) an oil phase, (c) anamphiphilic polyurethane polymer, and (d) an emulsifying agent, whereinthe polymer substantially forms a semipermeable shell layer around thewater molecules, and; contacting the resulting microcapsules with anaqueous buffered solution containing an additive, suitable to impart theadditive into the resulting microcapsule.

A further embodiment is directed towards a method of forming amicrocapsule composition comprising a plurality of microcapsules: saidplurality of microcapsules being formed by combining a polymer and atleast one buffered aqueous solution comprising a therapeutic agent, bycontacting: (a) said buffered solution containing the therapeutic agent,(b) an oil phase, (c) said polymer, and (d) an emulsifying agent,wherein the polymer substantially forms a semipermeable shell around thebuffered aqueous solution; and adding said plurality of microcapsules toa carrier.

In a preferred embodiment, said buffered solution is in contact with thesemipermeable shell.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an epifluorescent microscopic image of a microcapsulecontaining FITC-labeled lysozyme in PBS. The imaged microcapsule isapproximately 7 micrometers in size.

FIG. 2 is a confocal fluorescent imaging scan of a microcapsulecontaining FITC-labeled lysozyme in PBS. The imaged microcapsule isapproximately 7 micrometers in size. Without the use of a buffersolution, the lysozyme denatures and fluorescence is not observed.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides aqueous buffered microcapsule compositions fordelivering additives, including therapeutic and nontherapeutic agents,within a carrier. The nonlimiting description below sets forth variousembodiments of the subject compositions, and methods of making and usingsame, including for consumer care products, oral care products, skincare products, and other classes of products, using both therapeutic andadditive or nontherapeutic materials.

Production of Microcapsules

In a preferred embodiment, the composition of the invention is formed bycombining an aqueous buffered solution, an agent, an oil-solubleemulsifying agent, and at least one type of polymer which, when combinedand upon mixing or agitation, form the microcapsules of the invention.As used herein, the term “microcapsules” includes tiny particles ordroplets surrounded by a coating to give small capsules having usefulproperties. Microcapsules are sometimes referred to as microspheres,though a microcapsule of the invention need not be spherical in shape.The material inside the microcapsule shall be referred to herein by thesynonymous terms “core” and “internal phase,” and the materialsurrounding the core is referred to herein by the synonymous terms“shell,” “wall,” “coating,” “membrane,” and “exterior phase.” The shellneed not be completely or uniformly placed around the core of themicrocapsule, as long as substantially all of the core is surrounded bya polymer shell, as will be described further herein.

Preferably, the microcapsules of the invention have a diameter range ofbetween 100 nanometers and 3 millimeters. More preferably, the size ofthe microcapsules is between 1 micron and 1 mm. In general, thepreferable size of the microcapsule will be governed by the desired enduse application. One parameter used to control the size of themicrocapsules is by the amount and force of mixing or agitation of theemulsion. Other parameters to control the size of the microcapsules andcomponents of the microcapsules will be discussed further below. Thesize of the instant microcapsules can be optimized so that a sufficientnumber of microcapsules are available to affect a therapeutic response,or to release a sufficient amount of the additive for nontherapeuticembodiments.

Methods for constructing microcapsules may be physical or chemical.Physical methods include pan coating, air-suspension coating,centrifugal extrusion, vibrational nozzle and spray-drying. Chemicalmethods include polymerization such as interfacial polymerization,in-situ polymerization and matrix polymerization. In interfacialpolymerization, at least two monomers are dissolved separately inimmiscible liquids. Upon interface between the liquids, rapid reactionoccurs, creating a thin shell or wall of the microcapsule. In-situpolymerization is the direct polymerization of a single monomer carriedout on the particle's surface. In matrix polymerization, a core materialis embedded during formation of the microcapsule. Microcapsules mightalso be constructed by using sol-gel techniques, by aqueous or organicsolution precipitation synthesis methods, complex coacervation, and byother methods known in the art.

A preferred method of preparing the instant microcapsules is a synthesisto generate microcapsules containing buffer solutions of additives ortherapeutic agents, and in particular, antimicrobial agents. In order toencapsulate buffered solutions of biologically active additives in amicrocapsule, a surfactant-free inverse emulsion of water in oil ispreferably used. Any continuous oil phase can be used for the process ofthe invention. In one embodiment, hydrophobic oils are used as thecontinuous oil phase within the process with an emulsifying agent thatserves to sterically stabilize the dispersed phase. One preferred oilphase of the invention is methyl benzoate. FIG. 1 is an epifluorescentmicroscopic image of a microcapsule containing FITC-labeled lysozyme inPBS. The imaged microcapsule is approximately 7 micrometers in size.FIG. 2 is a confocal fluorescent imaging scan of a microcapsulecontaining FITC-labeled lysozyme in PBS. The imaged microcapsule isapproximately 7 micrometers in size.

A standard emulsion uses a surfactant to stabilize a dispersed droplet,whereas the present preferred method uses an emulsifying agent in acontinuous oil phase to sterically stabilize the dispersed waterdroplets in order to allow an interfacial polymerization to occur.

This causes an effective synthesis of polymer shells around the bufferedtherapeutic agent solution in the dispersed phase. The amphiphiliccharacter of surfactants causes interference with the polymerizationthat needs to occur at the interface of the dispersed phase and thecontinuous phase that is necessary to generate a capsule. A surfactantalso presents a problem in its affinity for ions. The polar hydrophilichead group could be attracted to certain types of the therapeutic agentsor the ions contained in the capsule for buffering the biologicallyactive additive. The presence of a surfactant decreases the percentageof, for example, ionic therapeutic agents that are truly bioavailable,effectively behaving as a chelation agent inactivating the release ofthe therapeutic agent from the capsule if the therapeutic agent is ionicin nature. Consequently, surfactant-free inverse emulsion interfacialpolymerization is preferred as the method for forming the instantmicrocapsules of the invention.

Emulsifying Agents

The emulsifying agents preferred in the microcapsules of the inventionare different from surfactants in that the emulsifying agentsexclusively partition into the oil phase and are not surface active.Inherent in the concept of using surfactant-free inverse emulsions isthat water droplets can be disrupted into small droplets, the size andsize distribution of which are dependent on the form and amount of inputenergy, and the droplets formed survive transiently due to a rathersluggish growth rate. Although surfactant-free emulsions have beenfrequently applied in solvent extraction, emulsion polymerization, andfood production such as oil-and-vinegar dressing production, very littleattention has been paid to its fundamental properties for use inmicroencapsulating buffered aqueous therapeutic agent solution systems.The emulsifying agent sterically stabilizes droplets without interferingwith interfacial polymerization.

Polymers

The microcapsules of the invention contain a shell comprised of at leastone polymer, preferably with the shell being semipermeable to particulartherapeutic agents, whether in buffered solutions. As used herein, theterms “polymer” and “polymers” are intended to connote precursor polymermolecules having a preferable size in the range of 1,000 to 50,000g/mole; more preferably from 1,500 to 20,000 g/mole; and more preferablyfrom 1,500 to 8,000 g/mole. Larger polymers can be used, as well assmaller oligomers or prepolymers, but the molecular weight of thepolymer is controlled for practical uses in the desired productapplications. Conceivably, monomers can be used as well in the method ofthe invention. A number of polymers can be combined into onemicrocapsule in order to produce an end use product having particularlydesired release characteristics of the core components. Accordingly, twoor more polymers can be combined together to generate a specific releaseprofile, or to generate a shell that will rupture, biodegrade, orrelease the contents within the microcapsule through a semipermeableshell, as desired.

In one embodiment of the invention, the microcapsule shell is designedwith limited or substantially no permeability depending on its desiredapplication. The impermeable shell is formed during synthesis byselecting particular polymers known to be impermeable to the particulartherapeutic agents in the desired end use application. Suchmicrocapsules may, for example, be synthesized for “burst” applicationas discussed herein. Such burst applications may be biodegradable, i.e.they will burst over time, or nonbiodegradable, wherein they areintended to burst upon a mechanical application to the microcapsules.

In further embodiments, the microcapsules are nonbiodegradable, but havea fast release profile, once outside of their carrier. For example, whenthe microcapsules are within a skin creme carrier, or within a soapbased carrier, (as nonlimiting examples of carriers) the release istempered. However, upon application of the skin creme, or soap, therelease from within the microcapsules is accelerated and results in ahighly permeable surface to release the contents of the microcapsule.Any of the suitable carriers, as described herein, can be utilized forsuch an embodiment.

Alternatively biodegradable polymers can be used, wherein uponapplication of the microcapsule to a surface, the microcapsule willdegrade and result in complete release of the microcapsule contents. Incertain embodiments, the microcapsule is semipermeable and alsodegrades, thus allowing for a slow initial release followed by aneventual burst application to release the remaining contents of themicrocapsule. In other embodiments, the microcapsule is nonpermeable andonly releases upon burst of the microcapsule.

Many classes of polymers can be used in the scope of the invention andthe choice depends on the specific desired properties. Examples include,but are not limited to, acrylic polymers, alkyl resins, aminoplasts,coumarone-indene resins, epoxy resins, fluoropolymers, phenolic resins,polyacetals, polyacetylenes, polyacrylics, polyalkylenes,polyalkenylenes, polyalkynylenes, polyamic acids, polyamides,polyamines, polyanhydrides, polyarylenealkenylenes,polyarylenealkylenes, polyarylenes, polyazomethines, polybenzimidazoles,polybenzothiazoles, polybenzoxazinones, polybenzoxazoles, polybenzyls,polycarbodiimides, polycarbonates, polycarboranes, polycarbosilanes,polycyanurates, polydienes, polyester-polyurethanes, polyesters,polyetheretherketones, polyether-polyurethanes, polyethers,polyhydrazides, polyimidazoles, polyimides, polyimines,polyisocyanurates, polyketones, polyolefins, polyoxadiazoles,polyoxides, polyoxyalkylenes, polyoxyarylenes, polyoxymethylenes,polyoxyphenylenes, polyphenyls, polyphosphazenes, polypyrroles,polypyrrones, polyquinolines, polyquinoxalines, plysilanes,polysilazanes, polysiloxanes, polysilsesquioxanes, polysulfides,polysulfonamides, polysulfones, polythiazoles, polythioalkylenes,polythioarylenes, polythioethers, polythiomethylenes,polythiophenylenes, polyureas, polyurethanes, polyvinyl acetals,polyvinyl butyrals, and polyvinyl formals. One skilled in the art willfurther appreciate that the selection of the specific type of polymerwill affect the composition and permeability characteristics of thesubject microcapsules.

Buffers

Buffers have a vast significance in all areas of science. A bufferedsolution resists changes in pH when acids or bases are added or whendilution occurs. A buffer is a mixture of an acid and its conjugatebase. There must be comparable amounts of the conjugate acid and base,within a factor of 10, to exert significant buffering. Buffers allow forthe proper functioning of any biological system and its subcellularcomponents such as proteins and peptide-based molecules. Nearly allbiological systems depend on pH. For example, a buffer solutionmaintains the correct pH for enzymes in many organisms to work.Typically, enzymes function only under very precise conditions. If thepH moves outside of a narrow range, the enzymes slow or stop functioningand can denature. pH directly affects the rate of enzyme-catalyzedreactions.

In some cases, the buffering of a therapeutic agent solution is requiredand in other cases the buffering of a therapeutic agent solution ispreferred to enhance shelf life and stability of a product. In somecases, the buffering of a therapeutic agent solution is preferred togain a more substantive effect of the agent. The rate of therapeuticagent release is a critical factor in patient care. This inventionprovides methods and compositions targeted at the microencapsulation ofa buffered therapeutic solution capable, for example, of a sustained,prolonged release of the therapeutic agent, a burst release of thetherapeutic agent, or a selective variable rate of release of thetherapeutic agent (e.g., a quick burst followed by sustained release, orsustained release followed by a quick burst).

Many classes of buffer solutions can be used in the invention, and thechoice of buffer depends on the specific pH desired. Examples include,but are not limited to, the following: Phosphate buffered saline whichis a solution containing sodium chloride, sodium phosphate, and, in someformulations, potassium chloride and potassium phosphate;3-([tris(hydroxymethyl)methyl]amino) propane-sulfonic acid (TAPS);N,N-bis(2-hydroxyethyl)glycine (Bicine);tris(hydroxyl-methyl)methylamine (Tris);N-tris(hydroxymethyl)methylglycine (Tricine);3-[N-Tris-(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid(TAPSO); 4-2-hydroxy-ethyl-1-piperazineethane sulfonic acid (HEPES);2-([tris(hydroxymethyl)methyl]amino) ethanesulfonic acid (TES);3-(N-morpholino)propanesulfonic acid (MOPS);piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES); dimethylarsinic acid(Cacodylate); saline sodium citrate (SSC);2-(N-morpholino)ethanesulfonic acid (IVIES); Phosphoric acid; citricacid; piperazine-N,N′-bis(3-propanesulfonic acid (PIPPS);piperazine-N,N′-bis(3-butanesulfonic acid) (PIPBS);N,N′-Diethylethylenediamine-N,N′-bis(3-propanesulfonic acid) (DESPEN);N,N′-di ethyl piperazine dihydrochloride (DEPP-2HC1);N,N,N′,N′-tetraethyl-ethylenediamine dihydrochloride (TEEN-2HC1);N-2-Acetamidoiminodiacetic acid (ADA);1,3-Bis[tris(hydroxymethyl)methylamino]propane hydrochloride (BIS-TRISpropane.HCl); N-2-acetamido-2-aminoethanesulfonic acid (ACES);3-(N-Morpholino)-2-hydroxypropanesulfonic acid (MOPSO); imidazolehydrochloride; 3-(N-morpholino)butanesulfonic acid (MOBS);4-2-hydroxyethyl-1-piperazinepropane-sulfonic acid (HEPPS);N-tris(hydroxymethyl)methylglycine (TRICINE); glycine amidehydrochloride; Tris(hydroxymethyl)aminomethane hydrochloride (TRIShydrochloride); glycylglycine; Boric acid; cyclohexylaminoethanesulfonicacid (CHES); 3-(Cyclohexylamino)propane sulfonic acid (CAPS);N,N,N′,N′-tetraethylmethylene-diamine dihydrochloride (TEMN-2HC1); HCland sodium citrate; citric acid and sodium citrate; acetic acid andsodium acetate; K₂HPO₄ and KH₂PO₄; Na₂HPO₄ and NaH₂PO₄;N-cyclohexyl-2-aminoethanesulfonic acid; sodium borate; and sodiumhydroxide.

It will be known to those skilled in the art that the buffer pH dependson ionic strength and temperature. Compositions can be adjustedaccordingly during the synthesis, storage and use of themicroencapsulated buffer solution. Preferred embodiments utilize abuffer within the range of pH 3 to pH 12, with preferred pH ranges ofbetween pH 4 and pH 11, and between pH 5 and pH 10. For example, it isknown that certain compounds have an increased solubility at a specificpH, and so the buffer can be formulated to increase or decreasesolubility, based on the desired result of the microcapsule.

Surfactant-Free Inverse Emulsion Polymerization

In a preferred embodiment of surfactant-free inverse emulsionpolymerization, a very low molecular weight polyurethane is premixedinto the continuous oil phase. Preferably, the molecular weight of thepolyurethane is 1,500 to 20,000 g/mole, and more preferably from 1,500to 8,000 g/mole. Due to the amphiphilic nature of the low molecularweight polyurethane, the polyurethane spends the majority of the time atthe interface of the dispersed and continuous phases. Accordingly, apreferred embodiment utilizes an amphiphilic polyurethane, having amolecular weight from between 1,500 to 20,000 g/mol, and moreparticularly from between 1,500 to 8,000 g/mol.

In this embodiment, diol is added to the system to increase themolecular weight of an isocyanate functionalized polyurethane shell. Apreferred diol is ethylene glycol. The diol ultimately leads to ethyleneoxide linker units in the microcapsule chemical structure. It has beenshown in industrial applications that ethylene oxide does not inhibitthe flow of ions between electrodes. This approach is useful forunderstanding the structure-property relationship of the urethane onmicrocapsule permeability due to the ease with which the chemicalstructure can be varied in the synthesis of the microcapsules by simplychanging the identity of the diol used in the polyurethane wall. In thisembodiment, the ion permeability of the microcapsule shell is based onthe chemical composition of the diols that act as spacer monomers. Thefollowing scheme represents the reaction used to synthesize themicrocapsule shell of this embodiment.

The length of the ethylene oxide spacer in the microcapsule wall may bevaried in order to control ion permeability of the membrane shell.Preferred embodiments include microcapsules using ethylene glycol (n=1)and from 1,4-butanediol (n=2). Preferred embodiments includemicrocapsules from diols where n=3 (1,6-hexanediol) or 4(1,8-octanediol). Preferred embodiments include microcapsules frompolymeric diols such as polyethylene glycol (also known as polyethyleneoxide or polyoxyethylene). Preferred embodiments include polyol monomerscapable of forming a crosslinked polymer microcapsule wall. Many classesof polyols can be used in the scope of the invention and the choicedepends on the specific desired properties. Examples include, but arenot limited to, pentaerythritol and glycerol.

In one embodiment, the microcapsule is biodegradable. The polyurethaneprepolymer could, for example, have a block of a polyester added to itto enhance biodegradation. Polylactic acid or polylactide could beincorporated into the microcapsule chemical structure to controlbiodegradation of the microcapsule. Those of skill in the art willrecognize the suitable biodegradable polymers, or combination ofpolymers sufficient to allow for degradation of the polymer shell.

A second characteristic influencing the permeability of the microcapsulemembrane is the shell or wall thickness, which may be varied by varyingthe ratio of the mass of material used to synthesize the shell to thevolume of the dispersed buffered therapeutic agent solution. At aconstant stir rate, adding more material relative to the bufferedaqueous therapeutic agent phase will lead to formation of thickermicrocapsule walls. In a preferred embodiment, the invention comprises aratio of 1 gram of polyurethane to from 15 to 40 mL of aqueous buffersolution.

We can modify the permeability by increasing the thickness of the shellwall, resulting in a decreased permeability. We can decrease thethickness of the shell wall to increase permeability. Modification ofthe parameters for forming the microcapsules can impart these changes.For example, we can modify the ratios of the polymer to the oil, we canreduce the concentration of the polymer, we can increase or decrease thereaction temperature, etc.

Brittleness of the microcapsules. We can also impact rupture of themicrocapsules by modifying the structure of the microcapsule to rupturebased upon the brittleness of the microcapsule. A polymer that has anyelasticity will resist rupture, and thus polymers that are intended toslow release and not burst, can be modified to be structured to reducethe risk of rupture, such as elasticity or thicker wall structure. Bycontrast, thin walled microcapsules, or those with brittle structure canbe mechanically ruptured.

Embodiments of the materials of the invention can be formulated suchthat only one type of buffered agent is contained within the core of themicrocapsule, or alternatively, a plurality of different types ofbuffered agents, and can be incorporated into one microcapsule.

In other embodiments, a plurality of microcapsules containing one typeof buffered additive can be combined in a product with microcapsulescontaining other additives.

In certain embodiments, a first microcapsule is formulated with a firstrelease profile and contains a first additive. A second microcapsules isformulated with a second release profile and contains either the samefirst additive or a second additive. This allows for a first release anda second release from a microcapsules composition of one or moreadditives. In certain embodiments, three, four, five, or more differentmicrocapsule formulations can be included in a single formulation, eachhaving the same or different release profile, and having the same ordifferent additives encapsulated therein.

Loading of Microcapsules

In preferred embodiments, the microcapsules of the invention containsemipermeable polymer shells wherein the permeability functions torelease an additive or therapeutic agent out of the microcapsules andinto the surrounding environment as a result of concentration gradients.Thus, embodiments are contemplated where already formed microcapsuleshaving none or less than the maximum possible amount of the additive ortherapeutic agent dissolved in the buffered solutions in the core can becharged with additional additive or therapeutic agent solution, hereinreferred to as “loading.” Loading also includes “recharging” ofmicrocapsules with buffered solution without therapeutic agents in thepresence of the target buffered therapeutic agent and appropriateconcentration gradients. The new additive or therapeutic agent can beintroduced into the core of partially loaded microcapsules orreintroduced into the core of empty microcapsules by immersing themicrocapsules into buffered solutions of highly charged therapeuticagents where the concentration of the additive or therapeutic agent inthe buffered solution is higher than the concentration of the additiveor therapeutic agent in the buffer solution within the core of themicrocapsules. The recharge rate of the microcapsules can depend on butis not limited to the following variables including the concentrationgradients of the additive or therapeutic agents, the temperature and therelease profile of the particular polymers of the product.

The method of loading a therapeutic agent into a microcapsule thatcontains only buffer solution is preferred when any heat above normalbody temperature is needed in the formation of the microcapsule. Thismethod avoids the use of heat that could cause a peptide-basedtherapeutic agent to denature.

The method of loading an additive into a microcapsule that contains onlybuffer solution is preferred when the temperature necessary to form themicrocapsule is higher than an appropriate temperature for the additive.For example, where an additive is volatile at a temperature within rangeof the microcapsule formation, the additive might be gassed off, orbecome instable when forming the microcapsules. Accordingly, use of asemipermeable microcapsule shell, and loading the additive to themicrocapsule through a higher concentration gradient, as describedabove, is appropriate for loading of the additive. Those of skill in theart will recognize the particular structure and volatility of theadditive and understand when such loading is necessary. Additionally,loading may be preferred wherein the addition of heat might degrade,damage, or modify the additive, but that loading, at a lowertemperature, would prevent such occurrence.

Therapeutic Agents

As used herein, the term “therapeutic agent” means an agent (e.g., anatom, an ion, a salt, a molecule (such as an inorganic molecule, anorganic molecule or a biomolecule (e.g., a peptide, a peptide analog ora protein)), a solid or a liquid) that brings about a beneficial effectto a mammal or any tissue or other subpart thereof.

Many classes of therapeutic agents can be used in the invention. Indeed,these therapeutic agents are envisioned for use in treating a wide arrayof conditions, such as demineralization of bone; weakness of bone, skin,hair and nails; drying, staining and cracking of skin; tooth sensitivityand discoloration; skin dehydration; and infections of all types.Examples of therapeutic agents include, but are not limited to, thevarious agents set forth below.

Antimicrobial Agents

Antimicrobial agents are substances that kill or inhibit the growth ofmicroorganisms such as bacteria, fungi or protozoa. Antimicrobial agentscan be in the form of a drug that is either microbiocidal ormicrobiostatic. Antimicrobial agents can be used outside the human bodyor on nonliving objects. Antimicrobial agents that are drugs can comefrom either natural sources or can be synthetically prepared.

Antimicrobial agents can also be used in many different products, suchas medical devices, wound dressings, fabrics, and numerous consumerproducts, both to protect the product itself (including the carrier)from antimicrobial growth or for public health, or cleaning purposes.Natural or synthetic antimicrobial materials have the potential to beincluded into other materials or used directly on product surfaces orcontained within a surface coating.

Natural antimicrobial agents include, but are not limited to, betalactam antibiotics such as penicillins or cephalosporins, proteinsynthesis inhibitors such as aminoglycosides, macrolides, ketolides,tetracyclines, chloramphenicol, and polypeptides. Penicillins include,but are not limited to, penicillin G, procaine penicillin, benzathinepenicillin, and penicillin V. Cephalosporins include, but are notlimited to, cefacetrile, cefadroxil, cephalexin, cefaloglycin,cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazaflur,cefazedone, cefazolin, cefradine, cefroxadine, ceftezole, cefaclor,cefonicid, cefprozil, cefuroxime, cefuzonam, cefmetazole, cefotetan andcefoxitin. Aminoglycosides include, but are not limited to, amikacin,arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin,rhodostreptomycin, streptomycin, tobramycin, and apramycin. Macrolidesinclude, but are not limited to, azithromycin, clarithromycin,dirithromycin, erythromycin, roxithromycin, and telithromycin. Ketolidesinclude, but are not limited to, telithromycin, cethromycin,solithromycin, spiramycin, ansamycin, oleandomycin, carbomycin andtylosin. Naturally occurring tetracyclines include, but are not limitedto, tetracycline, chlortetracycline, oxytetracycline, anddemeclocycline. Semisynthetic tetracyclines include, but are not limitedto, doxycycline, lymecycline, meclocycline, methacycline, minocyclineand rolitetracycline. Polypeptides include, but are not limited to,actinomycin, bacitracin, colistin, and polymyxin B. Syntheticantimicrobial agents include, but are not limited to, sulphonamides,cotrimoxazole, quinolones, antivirals, antifungals, anticancer drugs,antimalarials, antituberculosis drugs, antileprotics and antiprotozoals.Sulphonamide antibacterials may include, but are not limited to,sulfamethoxazole, sulfisomidine, sulfacetamide, sulfadoxine,dichlorphenamide, and dorzolamide. Sulphonamide diuretics include, butare not limited to, acetazolamide, bumetanide, chlorthalidone,clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside,metolazone, and xipamide. Sulphonamide anticonvulsants include, but arenot limited to, acetazolamide, ethoxzolamide, sultiame and zonisamide.Other sulfonamide therapeutic agents include, without limitation,celecoxib, darunavir, probenecid, sulfasalazine, and sumatriptan.

For example, use of antimicrobial agents would be helpful in soaps,detergents, cleaning sprays and the like. For example, a cleaningproduct contains a carrier and a cleaning agent within the carrier, andalso a plurality of microcapsules. The carrier and cleaning agent treata surface contacted by the carrier and reduce microbial populations.However, the microcapsules remain on the surface, or, bind to thesurface, and can continue to release additional antimicrobial agentsfrom the microcapsules.

Antifungal Agents

Common fungal infections include athlete's foot, ringworm, andcandidiasis. Fungi can also cause systemic infections like cryptococcalmeningitis. Antifungals work by exploiting differences between mammalianand fungal cells to kill off the fungal organism without dangerouseffects on the host. Unlike bacteria, both fungi and humans areeukaryotes. Other fungal issues are related to mold and the growth ofmold or other fungi in damp conditions.

Antifungal agents can be of the polyene type which includes, but is notlimited to, amphotericin B, candicidin, filipin, hamycin, natamycin,nystatin and rimocidin. Antifungal agents can be of the imidazole,triazole, and thiazole types which include, but are not limited to,bifonazole, butoconazole, clotrimazole, econazole, fenticonazole,isoconazole, ketoconazole, miconazole, omoconazole, oxiconazole,sertaconazole, sulconazole, tioconazole, albaconazole, fluconazole,isavuconazole, itraconazole, posaconazole, ravuconazole, terconazole,voriconazole and abafungin. Antifungal agents can also be echinocandinswhich can include, but are not limited to, anidulafungin, caspofunginand micafungin.

Preferred embodiments for antifungal agents include microcapsuleformulations that prevent the formation of mold. These formulations maybe used on towels, carpets, mats, showers, saunas, drains, or with otherareas or consumer products that see moisture. For example, materialsimpregnated with microcapsules, or compositions applied to the consumerproduct comprising the antifungal agent. Additional cleaning agents,soaps, detergents, and the like can also including antifungal agents.For example, a cleaning product contains a carrier and a cleaning agentwithin the carrier, and also a plurality of microcapsules. The carrierand cleaning agent treat a surface contacted by the carrier and reducemicrobial and/or fungal populations. However, the microcapsules remainon the surface, or, bind to the surface, and can continue to releaseadditional antifungal agents from the microcapsules, thus preventing thegrowth of the mold or mildew.

Antibacterial Agents

Host defense proteins and peptide-based antibiotic drugs can selectivelytarget and puncture the bacterial cell membrane. Host defense proteinswhich are part of the innate immune system in the body represent a firstline of defense against bacterial attack and primarily exist in therespiratory tract, urogenital tract, gastrointestinal track andepidermal tissues under the skin, all entry points for microbialpathogens in the body. These proteins kill bacteria by targetingbacterial membranes thereby generating an instability of the cellularcontents and membrane, which results in the death of the bacteria.Examples include the treatment of bacterial skin infections caused byStaphylococcus aureus, or the treatment of other blood streaminfections, lung infections and oral mucositis.

An approach to limiting the proliferation of microflora in the oralenvironment is through topical or systematic application ofbroad-spectrum antibacterial compounds. The reduction of the number oforal microflora in the mouth results in a direct reduction orelimination of plaque and pocket accumulation together with theirdamaging acidic metabolite production. The major drawback of thisparticular approach is that a wide variety of benign or beneficialstrains of bacteria are found in the oral environment which may bekilled by the same antibacterial compounds in the same manner as theharmful strains. In addition, treatment with antibacterial compounds mayselect for certain bacterial and fungi, which may then become resistantto the antibacterial compound administered and thus proliferate,unrestrained by the symbiotic forces of a properly balanced microflorapopulation. Thus, the application or administration of broad-spectrumantibiotics alone is ill-advised for the treatment of caries and a morespecific, targeted approach is desired.

The appearance of strains of drug-resistant bacteria and the increasednumber of drug-resistant infections has necessitated new approaches totreat these infections. There are many antibiotics in development fortreating resistant bacterial infections. Some of the emerging drugs arepeptide-based drugs and peptide analog-drugs. An effective method ofdelivery in an aqueous solution would be improved by storage in a buffersolution in order to improve shelf life and stability, along withleading to a more substantive effect of the therapeutic agent.

Additional antibacterial agents include, without limitation, copper (II)compounds such as copper (II) chloride, fluoride, sulfate and hydroxide,zinc ion sources such as zinc acetate, zinc citrate, zinc gluconate,zinc glycinate, zinc oxide, zinc sulfate and sodium zinc citrate,phthalic acid and salts thereof such as magnesium monopotassiumphthalate, hexetidine, octenidine, sanguinarine, benzalkonium chloride,domiphen bromide, alkylpyridinium chlorides such as cetylpyridiniumchloride (CPC) (including combinations of CPC with zinc and/or enzymes),tetradecylpyridinium chloride and N-tetradecyl-4-ethylpyridiniumchloride, iodine, halogenated carbanilides, halogenated salicylanilides,benzoic esters, halogenated diphenyl ethers, and mixtures thereof. Aparticularly suitable nonionic antibacterial agent is a diphenyl ethersuch as 2,4,4′-trichloro-2′-hydroxydiphenyl ether (Triclosan) and2,2′-dihydroxy-5,5′-dibromodiphenyl ether. Antifungal agents can be ofthe allylamines type which includes, but is not limited to, amorolfin,butenafine, naftifine and terbinafine.

For example, use of antibacterial agents might be useful in cleaningsupplies for hospital, personal care products, bandages, nursing homes,and the like. It is specifically envisioned that such agents would behelpful in soaps, detergents, cleaning sprays and the like. For example,a cleaning product contains a carrier and a cleaning agent within thecarrier, and also a plurality of microcapsules. The carrier and cleaningagent treat a surface contacted by the carrier and reduce microbial andbacterial populations. However, the microcapsules remain on the surface,or, bind to the surface, and can continue to release additionalantibacterial agents from the microcapsules that ensuring clean spaceswithout bacterial growth.

Antiviral Agents

Antivirals are used for specific viruses and are typically harmless tothe host. Many available drugs available are created to treat infectionsby retroviruses such as HIV. Important antiretroviral drugs include theclass of protease inhibitors. Herpes viruses, best known for causingcold sores and genital herpes, are usually treated with the nucleosideanalogue acyclovir. Viral hepatitis is caused by five unrelatedhepatotropic viruses and is also commonly treated with antiviral drugsdepending on the type of infection. Influenza A and B viruses areimportant targets for the development new influenza treatments toovercome the resistance to existing neuraminidase inhibitors such asoseltamivir.

Antiparasitic or Pesticide Agents

Antiparasitics are a class of medications which are indicated for thetreatment of infection by parasites, such as nematodes, cestodes,trematodes, infectious protozoa, and amoebae. Certain of theseantiparasitic compounds are useful both in medications for treatment ofspecific parasites, but also in topical applications to preventparasitic entry to a host. Similarly, destruction of the parasitesbefore they can reach a host serves to reduce or eliminate hostpopulations that might then transfer to a host.

Similarly, pesticides include agents targeting control of plant andanimal life forms that are pests to human, animal companions and toagriculture. This may include herbicides for destruction of weeks andunwanted vegetation, insecticides for controlling insect populations,fungicides for mold or mildew control, disinfectants for preventing thespread of bacteria, or compounds for treating small animal pestpopulations.

Antiparasitic agents include, but are not limited to: Broad-spectrum,Nitazoxanide, Antiprotozoals, Melarsoprol (for treatment of sleepingsickness caused by Trypanosoma brucei), Eflornithine (for sleepingsickness), Metronidazole (for vaginitis caused by Trichomonas),Tinidazole (for intestinal infections caused by Giardia lamblia),Miltefosine (for the treatment of visceral and cutaneous leishmaniasis,currently undergoing investigation for Chagas disease), Antihelminthic,Antinematodes, Mebendazole (for most nematode infections), Pyrantelpamoate (for most nematode infections), Thiabendazole (for roundworminfections), Diethylcarbamazine (for treatment of Lymphatic filariasis),Ivermectin (for prevention of river blindness), Anticestodes,Niclosamide (for tapeworm infections, Praziquantel (for tapeworminfections), Albendazole (broad spectrum), Antitrematodes, Antiamoebics,such as: Rifampin and Amphotericin B; Antifungals, such as Fumagillin(for microsporidiosis), alinia, benznidazole, daraprim, humatin,iodoquinol, nitazoxanide, paromomycin, pyrimethamine, tindamex,tinidazole, yodoxin. There are numerous other known agents that aresuitable for encapsulation herein.

Antimicrobial Coatings

A surface can be made antimicrobial by providing a coating containing anantibacterial agent that inhibits or diminishes the ability of amicroorganism to grow on the surface of a material. Surfacecontamination has become recognized as a health risk in various settingsincluding clinical, industrial and home. Antimicrobial coatings havebeen commonly used in the healthcare industry for sterilizing medicaldevices to prevent hospital-associated infections. Medical devices,surgical instruments, tubing, suture, tape, bandaging, linens andclothing provide a potential environment for many bacteria, fungi, andviruses to grow when in contact with the human body which allows for thetransmission of infectious disease. Likewise, implantable devices suchas pacemakers and subcutaneous rods provide environments for microbialgrowth, and would pose less risk of infection if treated with anantimicrobial coating. Antimicrobial surfaces can be functionalized in avariety of different processes. A coating may be applied to a surfacethat has a chemical compound which is toxic to a microorganism. Othersurfaces may be functionalized by attaching a polymer or polypeptide toits surface. In other cases, it is advantageous to have an encapsulatedaqueous solution of a peptide-based or peptide analog-basedantimicrobial agent embedded in a surface coating.

Specific Therapeutic Agents

ANTICOAGULANTS AND ANTITHROMBOTICS: Certain medical procedures exposepatients to life-threatening blood clots. Patients often receiveanticoagulant drugs that reduce or prevent the blood from clotting.Anticoagulant therapy is regularly administered and is a useful aid inthe recovery of most patients. However, the use of anticoagulantsincreases the risk of bleeding, while preserving a sufficient supply ofblood. Peptide-based and peptide analog-based drugs have exhibitedpromise in the maintenance of the antithrombosis/bleeding balance in thepatient. This is of value in procedures such as percutaneous coronaryintervention and coronary arterial bypass graft.

Anticoagulants include, but are not limited to, coumadins, heparins andits derivatives, low molecular weight heparins, syntheticpentasaccharide inhibitors such as fondaparinux and Idraparinux, directfactor Xa inhibitors, such as rivaroxaban and apixaban and directthrombin inhibitors including, but not limited to, hirudin, lepirudin,bivalirudin, argatroban and dabigatran.

ANTICANCER AGENTS: Therapeutic agents can also be anticancer agents,which include, but are not limited to, alkylating agents such asmechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide.Anticancer agents can be antimetabolites or plant alkaloids orterpenoids which include, but are not limited to, vincristine,vinblastine, vinorelbine and vindesine. Anticancer agents can includepodophyllotoxin or taxanes. Anticancer agents can be topoisomeraseinhibitors including, but not limited to, the camptothecins irinotecanand topotecan, amsacrine, etoposide, etoposide phosphate, andteniposide. Anticancer agents can be cytotoxic antibiotics that include,but are not limited to, actinomycin, anthracyclines, doxorubicin,daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin,and mitomycin. Antiprotozoals can include, but are not limited to,eflornithine, furazolidone, melarsoprol, metronidazole, ornidazole,paromomycin sulfate, pentamidine, pyrimethamine and tinidazole.

ANTI-INFLAMMATORY AGENTS: Anti-inflammatory agents include, but are notlimited to, flucinolone and hydrocortisone, ketorolac, flurbiprofen,ibuprofen, naproxen, indomethacin, diclofenac, etodolac, indomethacin,sulindac, tolmetin, ketoprofen, fenoprofen, piroxicam, nabumetone,aspirin, diflunisal, meclofenamate, mefenamic acid, oxyphenbutazone andphenylbutazone.

ANTIPLAQUE AGENTS: Antiplaque (e.g., plaque disrupting) agents can be aform of therapeutic agent. Suitable antiplaque agents include, withoutlimitation, glucoamylase and glucose oxidase.

DESENSITIZING AGENTS: Desensitizing, or tooth sensitivity-protectingagents, can be therapeutic agents. Desensitizing agents include, withoutlimitation, potassium salts such as potassium citrate, potassiumtartrate, potassium chloride, potassium sulfate and potassium nitrate orsodium nitrate.

SYSTEMIC ANALGESICS: Systemic analgesics include, but are not limitedto, aspirin, codeine, acetaminophen, sodium salicylate andtriethanolamine salicylate.

Drug Delivery and Indications Subcutaneous Drug Delivery

Biodegradable polymeric systems represent a promising method fordelivering many therapeutic agents, including, for example, peptides andpeptide analogs. Some polymers undergo a sol-gel transition onceadministered. A gel can form in situ in response to one or a combinationof stimuli including UV irradiation, pH change, temperature change, andsolvent exchange. Some polymeric systems have several advantages overconventional methods, including ease of manufacturing, ease ofadministration, and biodegradability. There have been challenges,however, to control the release profiles of the incorporated therapeuticagents. It would be advantageous to be able to store a peptide-based orpeptide analog-based drug in a microencapsulated buffer solution,wherein the semipermeable microcapsule could control the rate of releaseof the therapeutic agent. The microcapsule can be made to biodegradealong with the polymer system in which it is embedded.

Controlled Release

The microcapsules and products of the invention can be designed to havedifferent time release profiles, in such a way as to permit controlledtime release, also known as sustained release or long-term release, ofthe therapeutic agents or constituents to effectuate various desiredresults. Thus, various additives or components of the invention can bereleased at varying periods of time from each microcapsule. A pluralityof microcapsules that contain different concentrations can achieve, ineffect, a targeted therapeutic agent release profile.

Furthermore, the ratios of release times in different types ofmicrocapsules can be incorporated into the design of a single product tooptimize the permeability and concentration of the specific biologicallyactive additives or constituents of each type of microcapsule in theproduct relative to one another and relative to the environment wherethey are required. Such design enables a product that can deliver anumber of buffered therapeutic agents over a controlled time to aparticular targeted site without the need for numerous administrationsof a product to a patient, thereby minimizing the treatment regimen ofthe patient.

For example, a dental product can provide an antibacterial treatment toa targeted tooth surface in the oral cavity. For example, fillings,sealants and cements can be designed to contain the controlled releasemicrocapsules of the invention and to release buffered antimicrobialagents over time to the area of contact with the tooth or toothmaterial. Sustained release dosage forms of dental products avoid thenecessity of frequently administering an active while at the same timeachieving a desired level of anticaries activity in the oral cavity.

In a further example, a skin care product might have a salicylic acid ina first set of microcapsules, that has an immediate release, and then amoisturizing agent that has a sustained release. Thus, the salicylicacid would be effective immediately, and the moisturizing agent wouldmoisturize over the period of sustained release.

A further example might be towards a cleaning product, having a fastrelease of an antibacterial composition, and then a sustained release ofa scent. Accordingly, the antibacterial would clean the surface, and thescent would continue to release according to the sustained releaseprofile of the microcapsule. In other embodiments, the antibacterialcomposition might be in a slow release format, to ensure continualapplication of the material to eliminate bacteria from the surface beingcleaned, while a scent is in a separate microcapsule having the same ordifferent release profile.

One method for controlling release is selecting a shell polymer havingdesired permeability. Another method to control permeability and releaseprofile is to control the thickness of the shell layer during synthesisof the microcapsules as described herein.

The concentration of agents within the microcapsule can also be variedto effect permeability. In a preferred embodiment, buffered therapeuticagents and combinations thereof are incorporated in the microcapsules.Each microcapsule is synthesized with a buffered aqueous solution of atherapeutic agent with a specific targeted range of concentrations.

For example, tablets comprising the microcapsules of the invention canbe produced, wherein the therapeutic agent is not all immediatelyabsorbed, but instead is released gradually and continuously over aperiod of time from administration. For prolonged shelf life andsubstantive effects, the therapeutic agent is preferentially stored in abuffered solution.

In the oral cavity, an instant release or “burst” release of themicrocapsules can result upon mechanical agitation of the teeth, such asby use of toothbrushes or dental floss in the oral cavity; by regularchewing, grinding, gritting, clenching or clamping of the teeth or gums;by tongue motion or pressure of the tongue; or by swishing or garglingof liquids by the jaw muscles and motion of other muscles within theinternal orifices of the mouth. Both semipermeable microcapsules and theimpermeable microcapsules of the invention, as described above, can beincorporated into products designed for burst release effect.

Pharmaceutical Compositions

The compositions of this invention can be in the form of pharmaceuticalcomposition comprising the therapeutic agent-containing microcapsulesand a pharmaceutically acceptable carrier. Pharmaceutically acceptablecarriers are well known to those skilled in the art and include, but arenot limited to, 0.01-0.1 M and preferably 0.05 M phosphate buffer or0.8% saline. Additionally, such pharmaceutically acceptable carriers canbe aqueous or nonaqueous solutions, suspensions, and emulsions. Examplesof nonaqueous solvents or carriers are propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, and injectable organic esterssuch as ethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions and suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's and fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers such as Ringer's dextrose, those based onRinger's dextrose, and the like. Preservatives and other additives mayalso be present, such as, for example, antimicrobials, antioxidants,chelating agents, inert gases, and the like.

Bone Restorative Materials

The compositions of the invention are useful in a variety of bonerestorative or regeneration products. There is a need for new materialsthat can stimulate the body's own regenerative mechanisms and healtissues. Porous templates that act as scaffolds are thought to berequired for three-dimensional bone tissue growth. Bone growth factorshave high potential to stimulate bone-forming cells to produce new bone,they are degradable in the body and they bond to bone. Bone restorativeor regeneration products may include bone growth factors that could bestored longer or have more substantive effects if stored in a bufferedenvironment within the microcapsule.

Specific dental products comprising the microcapsules of the inventioninclude dental gels, pastes, rinses, dentifrices, whitening products,breath fresheners, artificial saliva systems, varnishes, desensitizersand other dental products well known in the dental art. Dentalrestorative materials include, but are not limited to, composite andother solid phase filling materials, adhesives and cements, temporaryrestorative materials, coatings on implants for the induction of bonegrowth. Various embodiments of the invention include over-the-counterapplications such as toothpastes, bleaching agents, varnishes, sealants,sealers, resin restorative materials, glass ionomers (including resinmodified glass ionomers), bioactive glass, compomer restorativematerials, giomer restorative materials, oral rinses, any topicalpreventive or remineralizing agents (liquids, gel mousses, pastes), anyrinse including antimicrobial agents, professionally applied andover-the-counter “paint-on” liquids gels, varnishes, sealers, indirectlaboratory materials including laboratory resins, denture teeth, denturebase materials, dental cements, root canal fillers and sealers,materials used for bone grafting, bone cements, dental implant tissuegrowth materials, endodontic root filling materials (i.e. apicoectomymaterials sometimes called retro-fill materials), pulp cappingmaterials, temporary restorative filling materials, prophy paste,periodontal scaling gels, air abrasion powders for prophylaxis,orthodontic cements, oral surgery extraction socket dressing, cadaverbone, and other bone substitutes.

Embodiments of dental products also include products that can dissolvein the oral cavity upon contact with saliva as a result of enzymaticactivity in the oral cavity, such as dissolvable whitening strips. Otherproducts incorporating the microcapsules that have a targeted effect onteeth include chewing gums, candies, lozenges, capsules, tablets andvarious food items.

In an embodiment where the microencapsulated dental compositions of thespecific buffered solutions of antimicrobial agents of the inventionallow incorporation of antimicrobial agents into a matrix ofpolymerizable composites and other solid filling dental restorativematerials such as glass ionomer cements, the incorporation of themicroencapsulated antimicrobial agents provides a source of bioactivefilling materials and adhesives. The use of semipermeable microcapsulesallows the material to release these antimicrobial agents at theinterface between the tooth structure and the restorative fillingmaterial or adhesive. This interface is particularly vulnerable tobacterial ingress, attack and subsequent secondary caries development.The presence of fluid within this interface can signal possiblemicroleakage at the restorative interface but also allow activation ofthe material to release the antimicrobial agents. Embodiments of themicrocapsules of the invention can be designed to release theantimicrobial agents when under mechanical stress at the opening of aspace at the tooth/filling interface.

Dental composition embodiments of the invention also comprise a solidphase, such as composites, which offer multiple advantages. Presently,it is unknown to add antimicrobial agents into a resin composite andprovide activity of the antimicrobial agents because the antimicrobialagents are likely incorporated or entombed within the resin or plasticinsoluble matrix.

Delivery and Indications for Subcutaneous and Topical Therapeutic AgentsRelated Therapeutic Products for Topical Use on Hair, Nails, Skin andOther Epithelial Tissue

There are numerous therapeutic agents that can be delivered to a subjectvia products such as moisturizers, creams, lotions, foams and gels. Suchagents include the following nonlimiting examples: antibacterials suchas Bactroban or Cleocin; Anthralin (Drithocreme, Micanol and others) forpsoriasis; antifungal agents such as Lamisil, Lotrimin and Nizoral forskin conditions such as ringworm and athlete's foot; benzoyl peroxidecreams for treating acne; coal tar for treating conditions such asseborrheic dermatitis (usually via shampoos) or psoriasis;corticosteroids for treating skin conditions including eczema via foams,lotions, ointments and creams; retinoids (such as Retin-A and Tazorac)are gels or creams for treating acne; salicylic acid in lotions, gels,soaps, shampoos, and patches, is used to treat acne and warts; antiviralagents such as Valtrex, acyclovir, and Famvir are useful for treatingherpes; corticosteroids such as prednisone, and immunosuppressants, suchas azathioprine and methotrexate, are useful in treating inflammatorydiseases such as eczema and psoriasis; and biologics such as Enbrel,Humira, Remicade, Stelara and Amevive are useful for treating psoriasisas well.

Additionally, nontherapeutic agents or additives can be advantageouslyencapsulated for use in these products. For example, it is appropriateto release a fragrance from a topical product. A moisturizer might usean encapsulated fragrance in a buffered solution to slowly release thefragrance from the moisturizer. This would give a pleasant scent to theuser, over a longer duration, instead of a short-lived and intense scentof nonencapsulated products.

SHAMPOO: A shampoo is made by combining a surfactant (typically sodiumlauryl sulfate and/or sodium laureth sulfate) with a cosurfactant(usually cocamidopropyl betaine) in water to form a thick, viscousliquid. Other shampoo components include salt (e.g., sodium chloride),preservatives and fragrances. Further components are usually added toachieve the following properties: pleasing foam; easy rinsing; minimalskin and eye irritation; thick and creamy feel; good fragrance; lowtoxicity; biodegradability; and proper pH.

The following are common shampoo ingredients: glycol distearate;silicone; ammonium chloride; ammonium lauryl sulfate; glycol; sodiumlauroamphoacetate (cleanser and counter-irritant); polysorbate 20(abbreviated as PEG(20), penetrant); polysorbate 80 (abbreviated asPEG(80), emulsifier); PEG-150 distearate (thickener); citric acid(antioxidant, pH adjuster and preservative); quaternium-15(preservative); polyquaternium-10 (conditioning agent); Di-PPG-2myreth-10 adipate (emollient); and methylisothiazolinone (MIT,preservative).

Many shampoos also include coloring agents, therapeutic/topical scalpagents, conditioners, moisturizers, and certainly fragrances. Byencapsulating these agents, release of the agents over a period of timecan be achieved that was not previously possible. For example a haircare product that aids in the prevention of grey hairs might include anencapsulated coloring agent. This coloring agent could bind to the hairand slowly release the coloring agent, thus preventing or reducing theappearance of grey hairs. Similar products are prevalent for facialhair.

For shampoos using a conditioning agent, the shampoo might first cleansethe hair, and the encapsulated conditioner can slowly release a leave-inconditioner to aid in prevention of knots in the hair. Such a productcould be especially useful for those with longer hair, children, orthose who frequently need to tie-up or cover their hair for religious orsanitary reasons, as nonlimiting examples.

HAIR CONDITIONER: Hair conditioners contain many types of ingredients.The following are examples: moisturizers (e.g., humectants);reconstructors (e.g., hydrolyzed protein); acidifiers; detanglers (e.g.,polymers); thermal protectors (e.g., heat-absorbing polymers); glossers(e.g., silicones such as dimethicone or cyclomethicone); oils (i.e.,essential fatty acids); surfactants (cationic); lubricants (e.g., fattyalcohols, panthenol, and dimethicone); sequestrants, for better functionin hard water; antistatic agents; and preservatives. Conditionersinclude, for example, the pack conditioners, leave-in conditioners,ordinary conditioners, and hold conditioners.

HAIR GEL: Hair gels, which contain cationic polymers, are hairstylingproducts that are used to stiffen hair into a particular hairstyle.Loading of microcapsules to release additional product throughout theday, could increase the length of the hold of the product. Furthermore,a hair gel could release conditioners, or coloring agents, or othertherapeutic or nontherapeutic additive to assist in maintenance of thehair.

HAIR COLORING AGENTS: While shampoos, as described above, might includecertain coloring agents. More particularly, hair dyes or colorantsinclude a peroxide and ammonia as primary components and the dye orcolor. Certain permanent dyes are either oxidation based or progressive.Progressive dyes typically contain lead acetate and bismuth citrate fortinting. Both agents work slowly by reacting with the sulfur of hairkeratin. Oxidation hair tint, by contrast, works by using the dyeintermediate p-phenylenediamine or 2-nitro-p-phenylenediamine, whichreact with the ammonia solution to bind and achieve the color.Accordingly, microcapsules could be used for several hair dye agents,namely as dye packets themselves, slowly and continually binding withkeratin, as a progressive dye.

As the ammonia and peroxide work synergestically, the ammonia acts as acatalyst for the peroxide, which binds pigment to the hair shaft. Thealkaline nature of the ammonia also tends to delaminate the hair shaft,allowing for greater penetration of pigment. The peroxide has adeleterious effect on hair by removing sulfur. This removal of sulfurhas a tendency to thin hair over time. However, if we can both bind dyeor pigment, and replace sulfur, we can preserve the volume of the hair.Accordingly, a microcapsule can be loaded with a sulfur containing agentto slowly provide sulfur to the hair strand. For example, microcapsulescould be designed to burst over time with the mechanical nature ofbrushing the hair, or by a slow-release, with the microcapsules bound tothe hair or skin to release agents onto the hair. Furthermore, we candeliver melanin to greying hair. Present research utilizes liposomes todeliver melanin to greying hair. We can replace the liposome with amicrocapsule, and use the microcapsule as the delivery mechanism for themelanin, thus providing semipermanent hair coloration.

MOISTURIZERS: Moisturizers increase the skin's hydration (water content)by reducing evaporation. Naturally occurring skin lipids and sterols aswell as artificial or natural oils, humectants, emollients, andlubricants, etc., may be part of the composition of commercial skinmoisturizers.

Moisturizers for preserving normal skin contain, e.g., lightweight oils,such as cetyl alcohol, or silicone-derived ingredients, such ascyclomethicone. Moisturizers for treating dry skin contain ingredientssuch as antioxidants, grape seed oil or dimethicone, and petrolatum (forvery dry skin). Moisturizers for treating the effects of aging contain,e.g., petrolatum, antioxidants and alpha hydroxy acids.

NAIL POLISH: Nail polishes typically contain phthalates (e.g.,dibutylphthalate [DBP], dimethylphthalate [DMP], diethylphthalate[DEP]), and toluene. However, nail polishes could include encapsulatedcoloring agents, to maintain the color of the polish over time. Indeed,nail polishes may include other agents or additives to strengthen thekeratin of the nail, prevent cracking of the nail, repair the nail, orrepair the colored polish.

For example a polish comprises encapsulated coloring agents which arebound to the dried polish. As the polish is agitated, the capsuleruptures, thus releasing the additional polish, thus preventing orreducing the appearance of a scratch on the nail surface.

Additives

As used herein, the terms “additive” and “therapeutic agent” are notmutually exclusive. Although many additives have no known therapeuticrole, some additives do have known therapeutic benefits. Certainadditives are specific towards non therapeutic, and hedonistic purposes,including for release of flavors, scents, colorants, conditioningagents, cleaning agents, fluorescing agents, odorants and deodorants,tactile agents, as nonlimiting examples.

In some embodiments, where oral application is desired, a sweetener isemployed in products that incorporate the microcapsule compositions ofthe present invention. Sweeteners among those useful herein include,without limitation, orally acceptable natural or artificial, nutritiveor nonnutritive sweeteners. Such sweeteners include, without limitation,dextrose, polydextrose, sucrose, maltose, dextrin, dried invert sugar,mannose, xylose, ribose, fructose, levulose, galactose, corn syrup(including high fructose corn syrup and corn syrup solids), partiallyhydrolyzed starch, hydrogenated starch hydrolysate, sorbitol, mannitol,xylitol, maltitol, isomalt, aspartame, neotame, saccharin and saltsthereof, sucralose, dipeptidebased intense sweeteners, cyclamates,dihydrochalcones, and mixtures thereof. One or more sweeteners can bepresent in a total amount depending strongly on the particularsweetener(s) selected.

Products incorporating the compositions of the present invention, whereoral application is desired, optionally comprise a flavoring agent.Flavoring agents among those useful herein include any material ormixture of materials operable to enhance the taste of the composition.Any orally acceptable natural or synthetic flavorant can be used, suchas flavoring oils, flavoring aldehydes, esters, alcohols, similarmaterials, and combinations thereof. Flavoring agents include vanillin,sage, marjoram, parsley oil, spearmint oil, cinnamon oil, oil ofwintergreen (methyl salicylate), peppermint oil, clove oil, bay oil,anise oil, eucalyptus oil, citrus oils, fruit oils and essencesincluding those derived from lemon, orange, lime, grapefruit, apricot,banana, grape, apple, strawberry, cherry, pineapple, etc., bean- andnut-derived flavors such as coffee, cocoa, cola, peanut, almond, etc.,adsorbed and encapsulated flavorants, and mixtures thereof. Alsoencompassed within flavoring agents are ingredients that providefragrance and/or other sensory effect in the mouth, including cooling orwarming effects. Such ingredients include, for example, menthol, menthylacetate, menthyl lactate, camphor, eucalyptus oil, eucalyptol, anethole,eugenol, cassia, oxanone, a-irisone, propenyl guaiethol, thymol,linalool, benzaldehyde, cinnamaldehyde, N-ethyl-p-menthan-3-carboxamine,N,2,3trimethyl-2-isopropylbutanamide, 3-1-menthoxypropane-1, 2-diol,cinnamaldehyde glycerol acetal (CGA), methone glycerol acetal (MGA), andmixtures thereof.

In some embodiments of the invention, the therapeutic agent is a“systemic active” which is used to treat or prevent a disorder which, inwhole or in part, is not a disorder of the oral cavity. In variousembodiments, the active is an “oral care active” used to treat orprevent a disorder or provide a cosmetic benefit within the oral cavity(e.g., to the teeth, gingiva or other hard or soft tissue of the oralcavity). Oral care actives among those useful in the dental compositionsherein include anticaries agents, tartar control agents, periodontalactives, abrasives, breath freshening agents, malodor control agents,tooth desensitizers, salivary stimulants, and combinations thereof. Itis understood that while general attributes of each of the abovecategories of therapeutic agent may differ, there may some commonattributes and any given material may serve multiple purposes within twoor more of such categories of agents. These therapeutic agents maypreferably be stored in a buffered solution to improve shelf life andprovide more substantive effects.

Products comprising the compositions of the present invention optionallycomprise an antioxidant. Any orally acceptable antioxidant can be used,including butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), vitamin A, carotenoids, vitamin E, flavonoids, polyphenols,ascorbic acid, herbal antioxidants, chlorophyll, melatonin, and mixturesthereof. Products comprising an antioxidant may preferably store thecomposition containing the antioxidant in a buffered solution to improveshelf life and provide more substantive effects.

Products containing compositions of the present embodiments optionallycomprise an orally acceptable zinc ion source useful, for example, as anantimicrobial, anticalculus or breath freshening agent. One or more suchsources can be present. Suitable zinc ion sources include, withoutlimitation, zinc acetate, zinc citrate, zinc gluconate, zinc glycinate,zinc oxide, zinc sulfate, sodium zinc citrate and the like. The productsof the invention can optionally comprise a suitable pH-adjusting agent,including, but not limited to, sodium hydroxide, potassium hydroxide,and ammonium, for controlling the stability and shelf life of a dentalproduct.

Products such as food materials incorporating the compositions of thepresent embodiments optionally comprise a nutrient. Suitable nutrientsinclude vitamins, minerals, amino acids, and mixtures thereof. Vitaminsinclude Vitamins C and D, thiamine, riboflavin, calcium pantothenate,niacin, folic acid, nicotinamide, pyridoxine, cyanocobalamin,para-aminobenzoic acid, bioflavonoids, and mixtures thereof. Nutritionalsupplements include amino acids (such as L-tryptophane, L-lysine,methionine, threonine, levocarnitine and L-carnitine), lipotropics (suchas choline, inositol, betaine, and linoleic acid), fish oil (includingcomponents thereof such as omega-3 (N-3) polyunsaturated fatty acids,eicosapentaenoic acid and docosahexaenoic acid), coenzyme Q10, andmixtures thereof. Products comprising a nutrient or nutritionalsupplement may preferably store the composition containing the nutrientor nutritional supplement in a buffered solution to improve shelf lifeand provide more substantive effects.

In another embodiment of the invention, the products comprising themicrocapsules may further include an antibacterial agent for releaseonto the bone tissue or dental surface. A wide variety of antimicrobialactive compounds may be employed. These actives may generally beclassified as halogenated hydrocarbons, quaternary ammonium salts andsulfur compounds. Halogenated hydrocarbons include halogenatedderivatives of salicylanilides, carbanilides, bisphenols, diphenylethers, anilides of thiophene carboxylic acids and chlorhexidines.Quaternary ammonium compounds include alkyl ammonium, pyridinum, andisoquinolinium salts. Sulfur active compounds include thiuram sulfidesand dithiocarbamates. Products comprising an antibacterial agent maypreferably store the composition containing the antibacterial agent in abuffered solution to improve shelf life and provide more substantiveeffects.

In various embodiments of the dental products of the present invention,the dental product comprises an adhesive or adhesion-enhancing agentwhich serves multiple functions, including enhancing adherence of acomposition to the surface of the tooth to be remineralized or whitened.The adhesives are optimized for adhering to the teeth, resistingadherence to non-tooth oral surfaces such as the lips, gingival or othermucosal surfaces, and remaining attached to the teeth for an extendedtime. Optimization of such aspects may be achieved from varying thephysical and chemical properties of a single adhesive or combiningdifferent adhesives. In certain embodiments of the present invention,the adhesive polymers in the product are those in which a dentalparticulate can be dispersed and are well known in the art.

The compositions of this invention can also be incorporated intocandies, lozenges, chewing gums, tablets, capsules or other products.Incorporation of the microcapsules into the product can be achieved by,for example, stirring into a warm gum base or coating the outer surfaceof a gum base, illustrative of which may be jelutong, rubber latex,vinylite resins, and similar compounds desirably with conventionalplasticizers or softeners, sugar, glucose, sorbitol or other sweeteners.It is also contemplated herein that the microcapsule compositions of thepresent invention can be incorporated into a variety of food items.

Each of the instant compositions, products and methods is envisioned forhuman use. It is also understood that although this specification refersspecifically to applications in humans, the invention is also useful forveterinary purposes. Thus, in all aspects, the methods and compositionsof the invention are useful for domestic animals such as cattle, sheep,horses and poultry; and for companion animals such as cats and dogs; aswell as for other animals.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to the specific embodiments that have beenparticularly shown and described hereinabove. Rather the scope of thepresent invention includes combinations of the features described aswell as modifications and variations thereof which would occur to aperson of skill in the art upon reading the foregoing description andwhich are not in the prior art.

In a further embodiment, a microcapsule formulation can be suitablyadded to numerous consumer products, and include one or more additivesalone, or additives and therapeutic agents, to improve physicalproperties, hedonistic properties, and aesthetic properties of suchmaterials.

For example, a laundry detergent with encapsulated fabric softenerdesigned to break open in the rinse cycle releasing the respectivefabric softener. Because of the incompatibility of many fabric softenerswith the typical laundry detergents when used simultaneously, thedetergent can first clean clothes, while the microcapsule releases thefabric softener upon the rinse cycle. This provides a single compositionsuitable for cleaning and softening clothes.

For example, rinse-cycle softeners usually contain cationic surfactantsof the quarternary ammonium family as the primary active ingredient,such as monoesterquat, diesterquat, trimethylamine diseterquat, and notcommonly used, distearyldimethylammonium chloride. These surfactantsbind well to natural fibers, but less so to synthetic fabrics. Animportant aspect of these softeners is that they are incompatible withanionic surfactants in detergents because they combine to form solidprecipitates. Accordingly, the detergent must be first added to the washcycle to clean clothes, and then the fabric softener added after therinse cycle to allow it to adhere to the fabric. Typically, thesesofteners contain 4-30% of active materials. In the present embodiments,laundry detergents can use a detergent as a carrier, and encapsulatedsofteners, which can be slowly released onto the fabric after the washphase. This would reduce or eliminate the need for the multi compartmentlaundry devices, and allow concentrated detergents (such as pods) toinclude both the detergent and the fabric softener in a single pod, orsingle liquid detergent. There are certain anionic fabric softeners, forexample salts of monoesters and diesters of phosphoric acid and fattyalcohols.

Laundry detergent with encapsulated fragrances that have an enduringodor release profile well beyond the wash cycle. For example, amicrocapsule can be designed to rupture at a specific temperature, onemet by the drying cycle, but not in the wash cycle. Accordingly,capsules will ‘burst upon drying’ if left out of the emulsion medium. Incertain embodiments, the capsules themselves could be dialed in so thatsome microcapsules are thicker than others and that property wouldimpart a “time lapse” release of the fragrance over an extended period.Accordingly, a first microcapsule could release in the dryer, providinga “fresh” scent, and additional capsules having a different releaseprofile would be bound to clothing and slowly release scent, or releasescent at a delayed rate as compared to the first microcapsule. Thisprovides long-lasting fresh smell to clothes.

It may also be suitable to encapsulate a wetting agent or a dryingagent. For example agents that promote moisture retention or moisture tothe microcapsule would be wetting agents. A drying agent could be asilica based agent or agent that would draw water into the microcapsuleor otherwise promote drying of the material.

Encapsulation of low solubility ingredients of any type, in an otherwiseaqueous based formula that would release through physical activity.Modification of the pH of the aqueous buffer solution can increase thesolubility of ingredients. Furthermore, prodrug style approaches, usinga molecule that will transition to the intended additive, or one that isgenerated through release of a first and second agent through twodifferent microcapsules is envisioned.

Encapsulated odor neutralizers used as an additive to cat litteractivated by burst technology upon the scratching activity of the cat.Simple encapsulation of absorbent materials, sodium bicarbonate, etc.can reduce the moisture and capture some of the odors. Indeed,additional deodorant based products are further envisioned, includingfor remedy of mold or mildew smells, as well as for deodorants andantiperspirant/deodorants for the body. Microcapsules can encapsulatetriclosan (antibacterial) cyclomethicones, sodium stearate, sodiumchloride, stearyl alcohol, EDTA, zinc oxide, ammonium chloride, sodiumbicarbonate, formaldehyde, or cyclopentasiloxane, or use of aluminumchlorohydrate, aluminum formate, aluminum zirconium tetrachlorohydrexglycine, potassium alum, ammonium alum, as commonly used components ofantiperspirants and deodorants.

Encapsulated fluorescing agents used in permanent dental/medicalmaterials. For example, where fluorescing agents are necessary forvisualizing certain aspects of a tooth surface, or in other medicalsettings, the fluorescing agents can be added to or bound to a surfaceof interest and provide a fluorescent cue.

Encapsulated slow release pesticides. For example, pesticides forbedding to combat bedbugs, pesticides for dog and cat applications,where the microcapsules bind to the hair or skin of the animal,pesticides for in-home use for treatment of floors or carpet againstfleas, mites, insects, arachnids, etc. Certain pesticides are alsosuitable for outdoor delivery for treatment of mosquitos, larva,beetles, arachnids, insects on ornamental plants and flowers. Release ofmaterials to prevent slug or snail infestation or other known pests.

Encapsulated slow release odorants to prevent insect or animal damage.Many animals are repelled by certain scents. Encapsulating these scentscould allow for slow release of such odorants to prevent damage toornamental plants or crops. For example, many current products seek toprevent small rodent, rabbit, and other small mammal damage. Others alsoseek to prevent deer damage, or other larger ungulate damage to plants.Through encapsulation of such odorant compounds, slow and timed releasecan appropriately be tailored to prevention of such damage.

Encapsulated substantive slow release hair dyes that ‘recover’ the addedcolor for an extended period.

Other classes of consumer products that may be appropriate formicroencapsulation technologies include, but are not limited to:detergents, dishwashing liquids, paper products, toilet tissues, facialtissues, towelettes, sanitary wipes, baby wipes, feminine products,dryer sheets, odor eliminating products, shaving creams, gels, foams,shampoos and conditioners, gels, hair sprays, foams, and other hair careproducts, cosmetic products, deodorants, antiperspirants, oral careproducts, lozenges, halitosis products, supplements, body soaps, skincare creams, lotions, and moisturizers, cleaning products and agents,diapers, diaper rash products, skin protectants, insect control, animalabsorbent products including paper and litter (cat litter, small animalbedding, etc.). Through the encapsulation of one of more components, asdescribed herein, consumer products can be ameliorated by providing fortimed release or delayed release of additional additives or agents thatwere not previously possible with the particular class of materials.

EXAMPLES

The following examples set forth the compositions and the synthesismethods of the invention. These experiments demonstrate the feasibilityof using the surfactant-free interfacial polymerization of a reverseemulsion to successfully encapsulate buffered solutions of therapeuticagents to create effective therapeutic compositions.

Example 1*

A microcapsule composition of the invention was prepared containing abuffered solution of a peptide-based anitimicrobial agent. Thecomposition was prepared by performing an interfacial polymerization ina stable inverse emulsion of phosphate buffer saline solution of apeptide-based antimicrobial agent in a methyl benzoate continuous phase.Six grams of polyglyceryl-3-polyricinoleate (P3P) was used as theemulsifying agent. The emulsifying agent and 4 grams of a polyurethanepolymer were mixed together. The aqueous buffer solution of thepeptide-based antimicrobial agent (100 mL of 0.1 M) was added to 210 mLof continuous methyl benzoate oil phase under mixing. 0.2 g of ethyleneglycol was subsequently added to the inverse emulsion to complete theinterfacial polymerization of the polyurethane polymer at the interfaceof the dispersed buffered aqueous solution of peptide-basedantimicrobial agent droplet. The average size of the microcapsule wascontrolled by the rate of mixing. Using the method of the invention, thefollowing buffered aqueous solutions of an antimicrobial agent werethereby prepared.

Example 2

A microcapsule composition of the invention was prepared containing abuffered solution of a peptide-based anitimicrobial agent. Thecomposition was prepared by performing an interfacial polymerization ina stable inverse emulsion of phosphate buffer saline solution in amethyl benzoate continuous phase. Six grams ofpolyglyceryl-3-polyricinoleate (P3P) was used as the emulsifying agent.The emulsifying agent and 4 grams of a polyurethane polymer were mixedtogether and added to 210 mL of continuous methyl benzoate oil phaseunder mixing. 0.2 g of ethylene glycol was subsequently added to theinverse emulsion to complete the interfacial polymerization of thepolyurethane polymer at the interface of the dispersed buffered aqueoussolution of a peptide-based antimicrobial agent. The microcapsulescontaining buffer solution were stirred in a solution of a bufferedpeptide-based antimicrobial agent (100 mL of 0.1 M) while being mixedand heated to 37° C. to effectively load the microcapsule with theantimicrobial agent. Using the method of the invention, the followingbuffered aqueous solutions of an antimicrobial agent were therebyprepared.

Example 3

A composition of the invention for cavity varnish with antimicrobialcapabilities was prepared as follows. A standard cavity varnishcontaining rosin, ethanol and thymol (97 wt %) were combined with 3 wt %of a microcapsule containing a 0.1 M buffered aqueous solution of anantimicrobial agent.

Example 4

A composition for toothpaste with antimicrobial capabilities wasprepared comprising a colloidal binding agent, humectants,preservatives, flavoring agents, abrasives, and detergents. 2 wt % of amicrocapsule containing a buffered aqueous solution of a peptide-basedantimicrobial agent was incorporated. The antimicrobial agents will bereleased from the encapsulated buffered solution to improvemineralization of the teeth.

Example 5

A composition for a dental resin composite with remineralization andtherapeutic capabilities was prepared as follows. A resin mixture (16 wt% total) was first made by combining urethane dimethacrylate resin withtriethyleneglycoldimethacrylate (TEGDMA) resin in a 4:1 ratio. Aphotosensitizer (camphoroquinone) was added at 0.7 wt % of the totalcomposition. An accelerator (ethyl-4-dimethylaminobenzoate) was added at3 wt % of the total composition. An inhibitor (4-methoxyphenol) wasadded at 0.05 wt % of the total composition. The resin, photosensitizer,accelerator and inhibitor were combined in a flask and mixed at 50° C.Upon homogenization, the above resin blend was mixed with the followingfillers (84 wt % total): silanated strontium glass 71 wt %, fumed silica10 wt %, microcapsules containing a buffered solution of peptide-basedantimicrobial agents.

Example 6

A shampoo having a delayed release scent. A microcapsule is formedcomprising an essence in an aqueous buffer solution. The microcapsule isformed through one of the methods described above. The microcapsule isadded to a commercial shampoo formulation. The microcapsule is designedfor a slow-release, to allow for fresh smelling hair over a period ofabout 24 hours.

Example 7

A laundry detergent having an antimicrobial microcapsule: A laundrydetergent is formulated comprising a water softener, a surfactant,bleach, enxymes, a brightener and a fragrance within a carrier. Amicrocapsule is formulated by the following method: A microcapsulecomposition of the invention was prepared containing a buffered solutioncomprising a quaternary ammonium monoesterquat. The composition wasprepared by performing an interfacial polymerization in a stable inverseemulsion of phosphate buffer saline solution in a methyl benzoatecontinuous phase. Six grams of polyglyceryl-3-polyricinoleate (P3P) wasused as the emulsifying agent. The emulsifying agent and 4 grams of apolyurethane polymer were mixed together and added to 210 mL ofcontinuous methyl benzoate oil phase under mixing. 0.2 g of ethyleneglycol was subsequently added to the inverse emulsion to complete theinterfacial polymerization of the polyurethane polymer at the interfaceof the dispersed buffered aqueous solution of a peptide-basedantimicrobial agent. The microcapsules containing buffer solution werestirred in a solution of quaternary ammonium monoesterquat (100 mL of1.0 M) while being mixed and heated to 37° C. to effectively load themicrocapsule with the fabric softener component.

A further modification of Example 7 includes a first microcapsule asprovided above in Example 7, and a second microcapsule formed by thesame process, but modifying one of the concentration of the polymer, theconcentration of the oil phase, or the temperature of formation, thusgenerating a different microcapsule having a slightly delayed releaseprofile as compared to the fabric softener. Within the secondmicrocapsule is a fragrance. Because of the slower release profile, thematerial would add the softener to the clothes and then release thefragrance over time.

Example 8

A deodorant comprising a plurality of microcapsules. A firstmicrocapsule comprising an aluminum based carrier and encapsulating anantibacterial agent, for delayed release of the antibacterial to preventodor.

Example 9

A pesticide composition comprising a carrier having within the carrier afirst pesticide, and a microcapsule comprising the same pesticide. Themicrocapsule formed as according to one of the methods provided herein,and generating a slow-release microcapsule to allow for slow release ofthe pesticide.

Example 10

A SLOW-RELEASE HAIR DYE: A peroxide and ammonia based carrier andencapsulating a pigment in an aqueous buffered solution. Themicrocapsule formed by any one of the methods as described herein, for aslow-release of pigment to the surface of the hair strand. A furtherexample includes a first microcapsule comprising a sulfur basedcomponent and a second microcapsule comprising a pigment. The first andsecond microcapsules having the same mechanical properties to allow forsynchronized release of the encapsulated agents to the hair strand. Thisallows for the sulfur to react with the pigment and bind to the hairstrand for extended color to the hair strand.

What is claimed is:
 1. A method of manufacturing a microcapsulecomprising: contacting an aqueous buffered solution comprising anadditive to an oil phase, an amphiphilic polyurethane polymer having amolecular weight between 1,000 g/mol to 20,000 g/mol, and an emulsifyingagent, forming a microcapsules through a surfactant-free inverseemulsion of water in oil, wherein the polymer substantially forms asemipermeable shell around the aqueous buffered solution and saidadditive.
 2. The method of claim 1 wherein the oil phase is ahydrophobic oil; and wherein the emulsifying agent that serves tosterically stabilize a dispersed phase.
 3. The method of claim 1 whereinthe oil phase is methyl benzoate.
 4. The method of claim 1 wherein thepolymer is selected from the group consisting of: acrylic polymers,alkyl resins, aminoplasts, coumarone-indene resins, epoxy resins,fluoropolymers, phenolic resins, polyacetals, polyacetylenes,polyacrylics, polyalkylenes, polyalkenylenes, polyalkynylenes, polyamicacids, polyamides, polyamines, polyanhydrides, polyarylenealkenylenes,polyarylenealkylenes, polyarylenes, polyazomethines, polybenzimidazoles,polybenzothiazoles, polybenzoxazinones, polybenzoxazoles, polybenzyls,polycarbodiimides, polycarbonates, polycarboranes, polycarbosilanes,polycyanurates, polydienes, polyester-polyurethanes, polyesters,polyetheretherketones, polyether-polyurethanes, polyethers,polyhydrazides, polyimidazoles, polyimides, polyimines,polyisocyanurates, polyketones, polyolefins, polyoxadiazoles,polyoxides, polyoxyalkylenes, polyoxyarylenes, polyoxymethylenes,polyoxyphenylenes, polyphenyls, polyphosphazenes, polypyrroles,polypyrrones, polyquinolines, polyquinoxalines, plysilanes,polysilazanes, polysiloxanes, polysilsesquioxanes, polysulfides,polysulfonamides, polysulfones, polythiazoles, polythioalkylenes,polythioarylenes, polythioethers, polythiomethylenes,polythiophenylenes, polyureas, polyurethanes, polyvinyl acetals,polyvinyl butyrals, polyvinyl formals, and combinations thereof.
 5. Themethod of claim 1 wherein the buffer solution comprises: phosphatebuffered saline which is a solution containing sodium chloride, sodiumphosphate, or potassium chloride, or potassium phosphate;3-([tris(hydroxymethyl)methyl]amino) propane-sulfonic acid (TAPS);N,N-bis(2-hydroxyethyl)glycine (Bicine);tris(hydroxyl-methyl)methylamine (Tris);N-tris(hydroxymethyl)methylglycine (Tricine);3-[N-Tris-(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid(TAPSO); 4-2-hydroxy-ethyl-1-piperazineethanesulfonic acid (HEPES);2-([tris(hydroxymethyl)methyl]amino) ethanesulfonic acid (TES);3-(N-morpholino)propanesulfonic acid (MOPS);piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES); dimethylarsinic acid(Cacodylate); saline sodium citrate (SSC);2-(N-morpholino)ethanesulfonic acid (IVIES); Phosphoric acid; citricacid; piperazine-N,N′-bis(3-propanesulfonic acid (PIPPS);piperazine-N,N′-bis(3-butanesulfonic acid) (PIPBS);N,N′-Diethylethylenediamine-N,N′-bis(3-propanesulfonic acid) (DESPEN);N,N′-diethylpiperazine dihydrochloride (DEPP-2HC1);N,N,N′,N′-tetraethyl-ethylenediamine dihydrochloride (TEEN-2HC1);N-2-Acetamidoiminodiacetic acid (ADA);1,3-Bis[tris(hydroxymethyl)methylamino]propane hydrochloride (BIS-TRISpropane-HCl); N-2-acetamido-2-aminoethanesulfonic acid (ACES);3-(N-Morpholino)-2-hydroxypropane sulfonic acid (MOPSO); imidazolehydrochloride; 3-(N-morpholino)butanesulfonic acid (MOBS);4-2-hydroxyethyl-1-piperazinepropane-sulfonic acid (HEPPS);N-tris(hydroxymethyl)methylglycine (TRICINE); glycine amidehydrochloride; Tris(hydroxymethyl)aminomethane hydrochloride (TRIShydrochloride); glycylglycine; Boric acid; cyclohexylaminoethanesulfonicacid (CHES); 3-(Cyclohexylamino)propane sulfonic acid (CAPS);N,N,N′,N′-tetraethylmethylene-diamine dihydrochloride (TEMN-2HC1); HCland sodium citrate; citric acid and sodium citrate; acetic acid andsodium acetate; K₂HPO₄ and KH₂PO₄; Na₂HPO₄ and NaH₂PO₄;N-cyclohexyl-2-aminoethanesulfonic acid; sodium borate; and sodiumhydroxide.
 6. The method of claim 1 wherein the buffer solution is at apH of between 3 and
 12. 7. The method of claim 1 further comprising adiol added to the semipermeable shell to increase the molecular weightof an isocyanate functionalized polyurethane shell.
 8. The method ofclaim 1 wherein the microcapsule is biodegradable.
 9. The method ofclaim 1 wherein the microcapsule is nonbiodegradable.
 10. The method ofclaim 1 wherein the emulsifying agent is in a continuous oil phase, saidemulsifying agent sufficient to sterically stabilize the dispersed waterdroplets to allow the formation of interfacial polymerization to formthe microcapsules.
 11. The method of claim 1 wherein the microcapsule isformulated into a shampoo, a conditioner, a hair gel, a hair foam, ashaving creme, a hair dye, a cleanser, a soap, a moisturizer, a paint, alacquer, a nail polish, a detergent, an insecticide, an antiparasitic,an antifungal, an antibacterial, a deodorant, and a pesticide.
 12. Themethod of claim 1 wherein the additive is a biologically active additiveor a peptide-based or peptide analog-based antimicrobial agent.
 13. Themethod of claim 1 wherein the additive is selected from the groupconsist of: menthol, menthyl acetate, menthyl lactate, camphor,eucalyptus oil, eucalyptol, anethole, eugenol, cassia, oxanone,a-irisone, propenyl guaiethol, thymol, linalool, benzaldehyde,cinnamaldehyde, N-ethyl-p-menthan-3-carboxamine,N,2,3trimethyl-2-isopropylbutanamide, 3-1-menthoxypropane-1, 2-diol,cinnamaldehyde glycerol acetal (CGA), methone glycerol acetal (MGA), andmixtures thereof.
 14. The method of claim 1 wherein the additive isselected from the group consist of: butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), vitamin A, carotenoids, vitamin E,flavonoids, polyphenols, ascorbic acid, herbal antioxidants,chlorophyll, melatonin, and mixtures thereof.
 15. The method of claim 1wherein the additive is selected from the group consist of: halogenatedhydrocarbons selected from: salicylanilides, carbanilides, bisphenols,diphenyl ethers, anilides of thiophene carboxylic acids, andchlorhexidines; quaternary ammonium compounds selected from: alkylammonium, pyridinum, and isoquinolinium salts; and Sulfur activecompounds selected from: thiuram sulfides and dithiocarbamates; andcombinations thereof.
 16. The method of claim 1 wherein the oil phase ismethyl benzoate and wherein the emulsifying agent ispolyglyceryl-3-polyricinoleate.
 17. The method of claim 12 wherein theanitimicrobial agents are selected from the group consisting of: naturalantimicrobial agents, beta lactam antibiotics such as penicillins orcephalosporins, protein synthesis inhibitors, aminoglycosides,macrolides, ketolides, tetracyclines, chloramphenicol, and polypeptides;penicillins include: penicillin G, procaine penicillin, benzathinepenicillin, and penicillin V; cephalosporins include: cefacetrile,cefadroxil, cephalexin, cefaloglycin, cefalonium, cefaloridine,cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin,cefradine, cefroxadine, ceftezole, cefaclor, cefonicid, cefprozil,cefuroxime, cefuzonam, cefmetazole, cefotetan, and cefoxitin;aminoglycosides include, but are not limited to, amikacin, arbekacin,gentamicin, kanamycin, neomycin, netilmicin, paromomycin,rhodostreptomycin, streptomycin, tobramycin, and apramycin; macrolidesinclude: azithromycin, clarithromycin, dirithromycin, erythromycin,roxithromycin, and telithromycin; ketolides include, but are not limitedto, telithromycin, cethromycin, solithromycin, spiramycin, ansamycin,oleandomycin, carbomycin, and tylosin; naturally occurring tetracyclinesinclude: tetracycline, chlortetracycline, oxytetracycline, anddemeclocycline; semisynthetic tetracyclines include, but are not limitedto, doxycycline, lymecycline, meclocycline, methacycline, minocycline,and rolitetracycline; polypeptides include, but are not limited to,actinomycin, bacitracin, colistin, and polymyxin B; syntheticantimicrobial agents include: sulphonamides, cotrimoxazole, quinolones,antivirals, antifungals, anticancer drugs, antimalarials,antituberculosis drugs, antileprotics, and antiprotozoals; sulphonamideantibacterials may include: sulfamethoxazole, sulfisomidine,sulfacetamide, sulfadoxine, dichlorphenamide, and dorzolamide;sulphonamide diuretics include: bumetanide, chlorthalidone, clopamide,furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, andxipamide; sulphonamide anticonvulsants include, but are not limited to,acetazolamide, ethoxzolamide, sultiame, and zonisamide; sulfonamidetherapeutic agents include: celecoxib, darunavir, probenecid,sulfasalazine, sumatriptan, and combinations thereof.
 18. The method ofclaim 1 wherein the additive is an antifungal agent and wherein saidantifungal agent is selected from the group consisting of: polyene type,amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, andrimocidin; imidazole, triazole, and thiazole types which include:bifonazole, butoconazole, clotrimazole, econazole, fenticonazole,isoconazole, ketoconazole, miconazole, omoconazole, oxiconazole,sertaconazole, sulconazole, tioconazole, albaconazole, fluconazole,isavuconazole, itraconazole, posaconazole, ravuconazole, terconazole,voriconazole, and abafungin; echinocandins including: anidulafungin,caspofungin, micafungin, and combinations thereof.
 19. The method ofclaim 1 wherein the additive is an antibacterial and wherein saidantibacterial additive is selected from the group consisting of: copper(II) compounds including: copper (II) chloride, fluoride, sulfate andhydroxide, zinc ion sources including: zinc acetate, zinc citrate, zincgluconate, zinc glycinate, zinc oxide, zinc sulfate and sodium zinccitrate, phthalic acid, and salts thereof including: magnesiummonopotassium phthalate, hexetidine, octenidine, sanguinarine,benzalkonium chloride, domiphen bromide, alkylpyridinium chloridesincluding: cetylpyridinium chloride (CPC) (including combinations of CPCwith zinc and/or enzymes), tetradecylpyridinium chloride andN-tetradecyl-4-ethylpyridinium chloride, iodine, halogenatedcarbanilides, halogenated salicylanilides, benzoic esters, halogenateddiphenyl ethers, and mixtures thereof; diphenyl ether including:2,4,4′-trichloro-2′-hydroxydiphenyl ether (Triclosan) and2,2′-dihydroxy-5,5′-dibromodiphenyl ether; allylamines agents including:butenafine, naftifine, terbinafine, and combinations thereof.
 20. Themethod of claim 1 wherein the additive is an antiparasitic agent,wherein the antiparasitic agent is selected from the group consistingof: Broad-spectrum, Nitazoxanide, Antiprotozoals, Melarsoprol,Eflornithine, Metronidazole, Tinidazole, Miltefosine, Antihelminthic,Antinematodes, Mebendazole, Pyrantel pamoate, Thiabendazole,Diethylcarbamazine, Ivermectin, Anticestodes, Niclosamide, Praziquantel,Albendazole, Antitrematodes, Antiamoebics, Rifampin, and Amphotericin B;Fumagillin, alinia, benznidazole, daraprim, humatin, iodoquinol,nitazoxanide, paromomycin, pyrimethamine, tindamex, tinidazole, yodoxin,and combinations thereof.